When patients relay their fantasies during psychotherapy sessions, those visions are often rooted in frustration or wish fulfillment, according to Jessica Ferranti, MD.
Dr. Jessica Ferranti
“[Sigmund] Freud talked about how our fantasy life is invested with large amounts of energy and interest and conveys a true essence of our personality – a truth about what we’re thinking and who we are,” Dr. Ferranti, a forensic psychiatrist in the division of psychiatry and the law at the University of California, Davis, said during an annual psychopharmacology update held by the Nevada Psychiatric Association.
“Fantasy life is one of the most important conveyances of information that we can get from our patients, whether in the general office or in the forensic realm – if we can access it, which is difficult, because fantasies are often intensely personal. They fall into the category of very high resistance topics with many patients.”
Psychiatrists routinely ask about violent thoughts and homicidal ideation, but violent fantasies – especially those that are sexually violent in nature – can be a warning sign of future danger. Dr. Ferranti defined violent fantasies as those depicting the use of physical force with the intent to injure another person or destroy property.
“This would be an individual who fantasizes about sadistically raping a woman, for instance,” said Dr. Ferranti, who directs the UC Davis Workplace Safety and Psychiatric Assessment Clinic. “That is an ominous and psychopathological sign in terms of the preoccupation with that kind of violent crime.”
Aggression, on the other hand, “is a very broad spectrum, with actions like assertion, interpersonal confrontation, or verbal expressions that are angry or hostile, but that do not necessarily lead to violence.”
Dr. Ferranti acknowledged that today’s rushed clinical environment makes it challenging for psychiatrists and psychologists to get patients to share detailed fantasies they may be harboring.
“It’s very difficult to get to deeper material with patients, unless potentially you have more intensive therapy going on, like a psychotherapeutic relationship where you see the patient frequently, an intensive treatment, [or] perhaps an inpatient hospitalization or a partial day program.” The key is that “the patient gets comfortable with relaying more of the truth about what they’re experiencing,” she said. “In some cases, this occurs during the forensic evaluation, because we have the luxury to do very lengthy evaluations. Under the stress of being with another person in the room for many hours, oftentimes the patient will disclose things eventually.
“I’ve been a forensic psychiatrist for the better part of 12 years, and I can tell you after hundreds of evaluations I’ve never had a person not speak. That’s a good thing, because a principle of the work we do, or talk therapy even, is that the things that we can put into words, we are less likely to act out. When we lose symbolism, the ability to represent things in our mind and speak about them, we are at greater risk of collapsing into the real and acting on the things we think about.”
Statutory reporting duties vary from state to state. In California, mandatory reporting duties include child abuse, elder abuse, abuse or neglect of developmentally disabled individuals, domestic violence, and victims of a gunshot wound. “Failing to report any of these crimes is a misdemeanor in California,” she said. “With all these statutory reporting duties, we have no legal obligation to inform the patient of the report. Under California law, patients do not have the right to refuse the report. These are reports we make in our best judgment, whether the patient is happy about that or not.”
What happens if your patient confesses to a past crime? “There’s no legal duty to report this,” Dr. Ferranti said. “The general rule is, unless there’s a current person who’s at risk, it would be violating confidentiality to report. This includes murder, bank robbery, and sexual assault. In addition, you cannot admit a patient to an inpatient setting to help them avoid arrest, even if you think the act in question was due to symptoms of a mental disorder, disease, or defect. You can actually be charged with aiding and abetting a criminal.”
In the 1976 landmark case Tarasoff v. the Regents of the University of California, the California Supreme Court ruled that psychiatrists and other therapists have a duty to do what is reasonably necessary to protect third parties if a patient presents a serious risk of violence to another person.
“Reasonable steps may include warning the third party, notifying police, detaining and hospitalizing the patient, intensifying the treatment to a higher level of care or more frequent outpatient appointments, removing weapons, and changing the medication therapy,” Dr. Ferranti said. “The more you can do of these, the better.”
She also discussed the concept of foreseeability, which she defined as the reasonable anticipation that harm or injury is likely to result from an act or omission to act.
“This is the malpractice standard for negligence,” she said. “In other words, was it foreseeable by a reasonable psychiatrist that this person was going to hurt someone else or themselves?” Another landmark case, Jablonski Pahls v. the United States broadened the reporting obligations of psychiatrists. In this 1983 case, the U.S. Court of Appeals 9th Circuit ruled that mental health professionals have to do more than warn foreseeable victims of an imminent danger of potential harm; they must involuntarily hospitalize the dangerous individual and consult that person’s prior records.
There is no sure-fire way to predict when an individual’s underlying violent fantasies are likely to be acted on, but Dr. Ferranti mentioned several behaviors that should raise alarm. One is a heightened physiological arousal when the person discusses the fantasy, such as rapid heartbeat, sweating; or physical posturing, such as clenching their fists or pounding their hands on an object as they tell you about it. You also want to determine the persistence of the fantasy.
“Can the patient think about it?” she asked. “Can they retain the ability to symbolize and separate themselves from necessarily doing whatever it is they think about?” You also want to determine the individual’s propensity for externalizing behaviors. “Here we’re talking about cluster B personality group patients – antisocial, narcissistic, and borderline patients who by virtue of their aggressivity titer and difficulties with anger, have a higher propensity for acting out and acting violently.”
Then there’s the concept of foreseeability. “Ask yourself, how likely is it that this could actually happen, based on the known risk factors and what you know about the patient?” Dr. Ferranti said. “Past history of violence is also very important. What people have done once before, they’re likely to do again.”
A good violence risk assessment can help you mitigate the potential for one of your patients to carry out harm to self or to others. Key risk factors include psychopathy, past violence, substance abuse, specific person/entity threatened, a history of impulsivity, unemployment, military history, gun possession, and the presence of paranoid and/or persecutory ideation or delusions.
“Know your specific state statutes and case law,” Dr. Ferranti concluded. “Delaying Tarasoff notification may indicate no need to violate confidentiality. If you think it’s warranted, do it without delay. Documentation is important when you’re consulting with therapists back and forth. You also want to attempt to obtain prior records and release only information that is required in a case of violence toward others. The details of the therapy or diagnosis are likely not relevant.”
When patients relay their fantasies during psychotherapy sessions, those visions are often rooted in frustration or wish fulfillment, according to Jessica Ferranti, MD.
Dr. Jessica Ferranti
“[Sigmund] Freud talked about how our fantasy life is invested with large amounts of energy and interest and conveys a true essence of our personality – a truth about what we’re thinking and who we are,” Dr. Ferranti, a forensic psychiatrist in the division of psychiatry and the law at the University of California, Davis, said during an annual psychopharmacology update held by the Nevada Psychiatric Association.
“Fantasy life is one of the most important conveyances of information that we can get from our patients, whether in the general office or in the forensic realm – if we can access it, which is difficult, because fantasies are often intensely personal. They fall into the category of very high resistance topics with many patients.”
Psychiatrists routinely ask about violent thoughts and homicidal ideation, but violent fantasies – especially those that are sexually violent in nature – can be a warning sign of future danger. Dr. Ferranti defined violent fantasies as those depicting the use of physical force with the intent to injure another person or destroy property.
“This would be an individual who fantasizes about sadistically raping a woman, for instance,” said Dr. Ferranti, who directs the UC Davis Workplace Safety and Psychiatric Assessment Clinic. “That is an ominous and psychopathological sign in terms of the preoccupation with that kind of violent crime.”
Aggression, on the other hand, “is a very broad spectrum, with actions like assertion, interpersonal confrontation, or verbal expressions that are angry or hostile, but that do not necessarily lead to violence.”
Dr. Ferranti acknowledged that today’s rushed clinical environment makes it challenging for psychiatrists and psychologists to get patients to share detailed fantasies they may be harboring.
“It’s very difficult to get to deeper material with patients, unless potentially you have more intensive therapy going on, like a psychotherapeutic relationship where you see the patient frequently, an intensive treatment, [or] perhaps an inpatient hospitalization or a partial day program.” The key is that “the patient gets comfortable with relaying more of the truth about what they’re experiencing,” she said. “In some cases, this occurs during the forensic evaluation, because we have the luxury to do very lengthy evaluations. Under the stress of being with another person in the room for many hours, oftentimes the patient will disclose things eventually.
“I’ve been a forensic psychiatrist for the better part of 12 years, and I can tell you after hundreds of evaluations I’ve never had a person not speak. That’s a good thing, because a principle of the work we do, or talk therapy even, is that the things that we can put into words, we are less likely to act out. When we lose symbolism, the ability to represent things in our mind and speak about them, we are at greater risk of collapsing into the real and acting on the things we think about.”
Statutory reporting duties vary from state to state. In California, mandatory reporting duties include child abuse, elder abuse, abuse or neglect of developmentally disabled individuals, domestic violence, and victims of a gunshot wound. “Failing to report any of these crimes is a misdemeanor in California,” she said. “With all these statutory reporting duties, we have no legal obligation to inform the patient of the report. Under California law, patients do not have the right to refuse the report. These are reports we make in our best judgment, whether the patient is happy about that or not.”
What happens if your patient confesses to a past crime? “There’s no legal duty to report this,” Dr. Ferranti said. “The general rule is, unless there’s a current person who’s at risk, it would be violating confidentiality to report. This includes murder, bank robbery, and sexual assault. In addition, you cannot admit a patient to an inpatient setting to help them avoid arrest, even if you think the act in question was due to symptoms of a mental disorder, disease, or defect. You can actually be charged with aiding and abetting a criminal.”
In the 1976 landmark case Tarasoff v. the Regents of the University of California, the California Supreme Court ruled that psychiatrists and other therapists have a duty to do what is reasonably necessary to protect third parties if a patient presents a serious risk of violence to another person.
“Reasonable steps may include warning the third party, notifying police, detaining and hospitalizing the patient, intensifying the treatment to a higher level of care or more frequent outpatient appointments, removing weapons, and changing the medication therapy,” Dr. Ferranti said. “The more you can do of these, the better.”
She also discussed the concept of foreseeability, which she defined as the reasonable anticipation that harm or injury is likely to result from an act or omission to act.
“This is the malpractice standard for negligence,” she said. “In other words, was it foreseeable by a reasonable psychiatrist that this person was going to hurt someone else or themselves?” Another landmark case, Jablonski Pahls v. the United States broadened the reporting obligations of psychiatrists. In this 1983 case, the U.S. Court of Appeals 9th Circuit ruled that mental health professionals have to do more than warn foreseeable victims of an imminent danger of potential harm; they must involuntarily hospitalize the dangerous individual and consult that person’s prior records.
There is no sure-fire way to predict when an individual’s underlying violent fantasies are likely to be acted on, but Dr. Ferranti mentioned several behaviors that should raise alarm. One is a heightened physiological arousal when the person discusses the fantasy, such as rapid heartbeat, sweating; or physical posturing, such as clenching their fists or pounding their hands on an object as they tell you about it. You also want to determine the persistence of the fantasy.
“Can the patient think about it?” she asked. “Can they retain the ability to symbolize and separate themselves from necessarily doing whatever it is they think about?” You also want to determine the individual’s propensity for externalizing behaviors. “Here we’re talking about cluster B personality group patients – antisocial, narcissistic, and borderline patients who by virtue of their aggressivity titer and difficulties with anger, have a higher propensity for acting out and acting violently.”
Then there’s the concept of foreseeability. “Ask yourself, how likely is it that this could actually happen, based on the known risk factors and what you know about the patient?” Dr. Ferranti said. “Past history of violence is also very important. What people have done once before, they’re likely to do again.”
A good violence risk assessment can help you mitigate the potential for one of your patients to carry out harm to self or to others. Key risk factors include psychopathy, past violence, substance abuse, specific person/entity threatened, a history of impulsivity, unemployment, military history, gun possession, and the presence of paranoid and/or persecutory ideation or delusions.
“Know your specific state statutes and case law,” Dr. Ferranti concluded. “Delaying Tarasoff notification may indicate no need to violate confidentiality. If you think it’s warranted, do it without delay. Documentation is important when you’re consulting with therapists back and forth. You also want to attempt to obtain prior records and release only information that is required in a case of violence toward others. The details of the therapy or diagnosis are likely not relevant.”
When patients relay their fantasies during psychotherapy sessions, those visions are often rooted in frustration or wish fulfillment, according to Jessica Ferranti, MD.
Dr. Jessica Ferranti
“[Sigmund] Freud talked about how our fantasy life is invested with large amounts of energy and interest and conveys a true essence of our personality – a truth about what we’re thinking and who we are,” Dr. Ferranti, a forensic psychiatrist in the division of psychiatry and the law at the University of California, Davis, said during an annual psychopharmacology update held by the Nevada Psychiatric Association.
“Fantasy life is one of the most important conveyances of information that we can get from our patients, whether in the general office or in the forensic realm – if we can access it, which is difficult, because fantasies are often intensely personal. They fall into the category of very high resistance topics with many patients.”
Psychiatrists routinely ask about violent thoughts and homicidal ideation, but violent fantasies – especially those that are sexually violent in nature – can be a warning sign of future danger. Dr. Ferranti defined violent fantasies as those depicting the use of physical force with the intent to injure another person or destroy property.
“This would be an individual who fantasizes about sadistically raping a woman, for instance,” said Dr. Ferranti, who directs the UC Davis Workplace Safety and Psychiatric Assessment Clinic. “That is an ominous and psychopathological sign in terms of the preoccupation with that kind of violent crime.”
Aggression, on the other hand, “is a very broad spectrum, with actions like assertion, interpersonal confrontation, or verbal expressions that are angry or hostile, but that do not necessarily lead to violence.”
Dr. Ferranti acknowledged that today’s rushed clinical environment makes it challenging for psychiatrists and psychologists to get patients to share detailed fantasies they may be harboring.
“It’s very difficult to get to deeper material with patients, unless potentially you have more intensive therapy going on, like a psychotherapeutic relationship where you see the patient frequently, an intensive treatment, [or] perhaps an inpatient hospitalization or a partial day program.” The key is that “the patient gets comfortable with relaying more of the truth about what they’re experiencing,” she said. “In some cases, this occurs during the forensic evaluation, because we have the luxury to do very lengthy evaluations. Under the stress of being with another person in the room for many hours, oftentimes the patient will disclose things eventually.
“I’ve been a forensic psychiatrist for the better part of 12 years, and I can tell you after hundreds of evaluations I’ve never had a person not speak. That’s a good thing, because a principle of the work we do, or talk therapy even, is that the things that we can put into words, we are less likely to act out. When we lose symbolism, the ability to represent things in our mind and speak about them, we are at greater risk of collapsing into the real and acting on the things we think about.”
Statutory reporting duties vary from state to state. In California, mandatory reporting duties include child abuse, elder abuse, abuse or neglect of developmentally disabled individuals, domestic violence, and victims of a gunshot wound. “Failing to report any of these crimes is a misdemeanor in California,” she said. “With all these statutory reporting duties, we have no legal obligation to inform the patient of the report. Under California law, patients do not have the right to refuse the report. These are reports we make in our best judgment, whether the patient is happy about that or not.”
What happens if your patient confesses to a past crime? “There’s no legal duty to report this,” Dr. Ferranti said. “The general rule is, unless there’s a current person who’s at risk, it would be violating confidentiality to report. This includes murder, bank robbery, and sexual assault. In addition, you cannot admit a patient to an inpatient setting to help them avoid arrest, even if you think the act in question was due to symptoms of a mental disorder, disease, or defect. You can actually be charged with aiding and abetting a criminal.”
In the 1976 landmark case Tarasoff v. the Regents of the University of California, the California Supreme Court ruled that psychiatrists and other therapists have a duty to do what is reasonably necessary to protect third parties if a patient presents a serious risk of violence to another person.
“Reasonable steps may include warning the third party, notifying police, detaining and hospitalizing the patient, intensifying the treatment to a higher level of care or more frequent outpatient appointments, removing weapons, and changing the medication therapy,” Dr. Ferranti said. “The more you can do of these, the better.”
She also discussed the concept of foreseeability, which she defined as the reasonable anticipation that harm or injury is likely to result from an act or omission to act.
“This is the malpractice standard for negligence,” she said. “In other words, was it foreseeable by a reasonable psychiatrist that this person was going to hurt someone else or themselves?” Another landmark case, Jablonski Pahls v. the United States broadened the reporting obligations of psychiatrists. In this 1983 case, the U.S. Court of Appeals 9th Circuit ruled that mental health professionals have to do more than warn foreseeable victims of an imminent danger of potential harm; they must involuntarily hospitalize the dangerous individual and consult that person’s prior records.
There is no sure-fire way to predict when an individual’s underlying violent fantasies are likely to be acted on, but Dr. Ferranti mentioned several behaviors that should raise alarm. One is a heightened physiological arousal when the person discusses the fantasy, such as rapid heartbeat, sweating; or physical posturing, such as clenching their fists or pounding their hands on an object as they tell you about it. You also want to determine the persistence of the fantasy.
“Can the patient think about it?” she asked. “Can they retain the ability to symbolize and separate themselves from necessarily doing whatever it is they think about?” You also want to determine the individual’s propensity for externalizing behaviors. “Here we’re talking about cluster B personality group patients – antisocial, narcissistic, and borderline patients who by virtue of their aggressivity titer and difficulties with anger, have a higher propensity for acting out and acting violently.”
Then there’s the concept of foreseeability. “Ask yourself, how likely is it that this could actually happen, based on the known risk factors and what you know about the patient?” Dr. Ferranti said. “Past history of violence is also very important. What people have done once before, they’re likely to do again.”
A good violence risk assessment can help you mitigate the potential for one of your patients to carry out harm to self or to others. Key risk factors include psychopathy, past violence, substance abuse, specific person/entity threatened, a history of impulsivity, unemployment, military history, gun possession, and the presence of paranoid and/or persecutory ideation or delusions.
“Know your specific state statutes and case law,” Dr. Ferranti concluded. “Delaying Tarasoff notification may indicate no need to violate confidentiality. If you think it’s warranted, do it without delay. Documentation is important when you’re consulting with therapists back and forth. You also want to attempt to obtain prior records and release only information that is required in a case of violence toward others. The details of the therapy or diagnosis are likely not relevant.”
For millennia, serious psychiatric brain disorders (aka mental illnesses, melancholia, madness, insanity) were written off as incurable, permanent afflictions. It’s no wonder that they were engulfed with the stigma of hopelessness.
But then came the era of serendipitous discoveries in the mid-20th century, with the felicitous arrival of antipsychotics, antidepressants, and lithium. The dogma of untreatability was shattered, but in its wake, the notion of treatment resistance emerged, and promptly became the bane of psychiatric clinicians and the practice of psychopharmacology.
Many patients with mood and psychotic disorders responded to the medications that were introduced in the 1950s and 1960s, but some either derived partial benefit or did not improve at all. These partial or poor responders were labeled “treatment-resistant,” and caring for them became a major challenge for psychiatric physicians that continues to this day. However, rapid advances in understanding the many etiologies and subtypes of the heterogeneous mood and psychotic disorders are invalidating the notion of treatment resistance, showing it is a fallacy and a misnomer. Let’s examine why.
Treatment-resistant depression (TRD)
Psychiatric clinics and hospitals are clogged with patients who do not respond to ≥2 evidence-based antidepressants and carry the disparaging label of “TRD.” But a patient manifesting what appears to be major depressive disorder (MDD) may actually have one of several types of depression that are unlikely to respond to an antidepressant, including:
iatrogenic depression due to a prescription medication
depression secondary to recreational drug use
depressive symptoms secondary to a general medical condition
bipolar depression.
Thus, a significant proportion of patients diagnosed with MDD are labeled TRD because they do not respond to standard antidepressants, when in fact they have been misdiagnosed and need a different treatment.
Even when the diagnosis of MDD is accurate, psychiatric neuroscience advances have informed us that MDD is a heterogeneous syndrome with multiple “biotypes” that share a similar phenotype.1,2 In the past, TRD has been defined as a failure to respond to ≥2 adequate trials (8 to 12 weeks at a maximum tolerated dose) of antidepressants from different classes (such as tricyclic or heterocyclic antidepressants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors). For decades, patients with TRD have been referred to electroconvulsive therapy (ECT), and have experienced an excellent response rate. So TRD is in fact an artificial concept and term, applied to a subtype of MDD that does not respond to standard antidepressants, but often responds very well to neurostimulation (ECT and transcranial magnetic stimulation [TMS]).
When an antidepressant is approved by the FDA based on “successful” placebo-controlled double-blind trials, there is always a subset of patients who do not respond. However, the success of a controlled clinical trial is based on a decline in overall mean depression rating scale score in the antidepressant group compared with the placebo group. Not a single antidepressant has ever exerted full efficacy in 100% of patients who received it in an FDA trial because the sample is always a heterogeneous mix of patients with various depression biotypes who meet the DSM clinical diagnosis of MDD. Most often, only approximately 50% do, which is enough to be statistically significantly better than the roughly 30% response rate in the placebo group. It is impossible for a heterogeneous syndrome comprised of biologically different “diseases” to respond to any single medication! Patients who do not respond to an antidepressant medication that works in other patients represent a different subtype of depression that is not TRD. Biotypes of the depression syndrome have different neurochemical underpinnings and may respond to different mechanisms of therapeutic action, yet to be discovered.
Continue to: A very common...
A very common clinical mistake occurs when patients with bipolar depression are misdiagnosed as having MDD because most of them experience depression as their initial mood episode. These patients often end up being classified as having TRD because bipolar depression very frequently fails to respond to several of the antidepressants that are FDA-approved for MDD. When these patients are correctly diagnosed, many will respond to one of the medications specifically approved for bipolar depression that were launched over the past 15 years (quetiapine, lurasidone, and cariprazine). However, bipolar disorder is also a heterogeneous spectrum, and some patients with bipolar depression may fail to respond to any of these 3 medications and are promptly regarded as TRD. Such patients often respond to neuromodulation (TMS, ECT, or vagus nerve stimulation [VNS]), indicating that they may have a different type of bipolar depression, such as bipolar type II.
A more recent example of the falsehood of TRD as a spurious diagnosis is the dramatic and rapid response of patients who are chronically depressed (both those with MDD and those with bipolar depression) to ketamine infusions.3,4 Responders to ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, prove that nonresponders to monoamine reuptake inhibitors must not be falsely labeled as having TRD. They have a different subtype within the depression syndrome that is mediated by glutamatergic pathways, instead of monoamines such as serotonin, norepinephrine, or dopamine. In addition, unlike monoaminergic antidepressants, NMDA antagonists rapidly reverse suicidal urges, above and beyond rapidly reversing chronic, so-called TRD.
In the same vein, numerous reports have shown that buprenorphine has significant efficacy in TRD (and suicide urges, as does ketamine), which implicates opioid pathways as mediating some subtypes of TRD.5 The monoamine model of depression, which dominated the field and dragged on for half a century, has distracted psychiatric researchers from exploring and recognizing the multiple neurochemical and neuroplastic pathways of the depression syndrome, thus falsely assuming that depression is a monolithic disorder that responds to elevating the activity of brain monoamines. This major blind spot led to the ersatz concept of TRD.
Treatment-resistant schizophrenia (TRS)
Since the discovery of chlorpromazine and other antipsychotics in the 1950s, it became apparent that a subset of patients with schizophrenia do not respond to medications that block dopamine D2 receptors. Partial responders were labeled as having TRS, and complete nonresponse was called refractory schizophrenia. Many patients with severe and persistent delusions and hallucinations were permanently hospitalized, and unable to live in the community like those who responded to dopamine antagonism.
In the late 1980s, the discovery that clozapine has significant efficacy in TRS and refractory schizophrenia provided the first insight that TRS and refractory schizophrenia represent different neurobiologic subtypes of schizophrenia.6,7 The extensive heterogeneity of schizophrenia (with hundreds of genetic and nongenetic etiologies) is now widely accepted.8 Patients with schizophrenia who do not respond to dopamine receptor antagonism should not be labeled TRS, because they can respond to a different antipsychotic agent, such as clozapine, which is believed to exert its efficacy via glutamate pathways.
Continue to: But what about the 50%...
But what about the 50% of patients with TRS or refractory schizophrenia who do not respond to clozapine?9 They do not have TRS, either, but represent different schizophrenia biotypes that may respond to other medications with different mechanisms of action, such as lamotrigine,10 which is a glutamate modulator; pimavanserin,11 which is an inverse agonist of the serotonin 5HT-2A receptor; allopurinol,12,13 an adenosine modulator; or estrogen,14 a neurosteroid. Future research will continue to unravel the many biotypes of the highly heterogeneous schizophrenia syndrome that are “nondopaminergic” and do not respond to the standard class of dopamine antagonists (previously called neuroleptics and now known as antipsychotics).15 Future treatments for schizophrenia may depart from modulating various neurotransmitter receptors to targeting entirely different neurobiologic processes, such as correcting mitochondria pathology, inhibiting microglia activation, repairing white matter, reversing apoptosis pathways, inducing neuroplasticity, arresting oxidative stress and inflammation, and other neuroprotective mechanisms.
The rapid growth of biomarkers in psychiatry16 will usher in an era of precision psychiatry17 that will eliminate the term “treatment resistance.” Our psychiatric practice will then benefit from “canceling” this demoralizing and clinically unjustified term that has needlessly fostered therapeutic nihilism among psychiatric physicians.
References
1. Milaneschi Y, Lamers F, Berk M, et al. Depression heterogeneity and its biological underpinnings: toward immunometabolism depression. Biol Psychiatry. 2020;88(5):369-380. 2. Akiskal HS, McKinney WT Jr. Overview of recent research in depression. Integration of ten conceptual models into a comprehensive clinical frame. Arch Gen Psychiatry. 1975;32(3):285-305. 3. Zarate CA Jr. Ketamine: a new chapter in antidepressant development. Brazilian J Psychiatry. 2020;42(6):581-582. 4. Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67(8):793-802. 5. Serafini G, Adavastro G, Canepa G, et al. The efficacy of buprenorphine in major depression, treatment-resistant depression and suicidal behavior: a systematic review. Int J Mol Sci. 2018;19(8):2410. 6. Potkin SG, Kane JM, Correll CU, et al. The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research. NPJ Schizophr. 2020;6(1):1. 7. Campana M, Falkai P, Siskind D, et al. Characteristics and definitions of ultra-treatment-resistant schizophrenia - a systematic review and meta-analysis. Schizophr Res. 2021;228:218-226. 8. Kinon BJ. The group of treatment resistant schizophrenias. Heterogeneity in treatment-resistant schizophrenia (TRS). Front Psychiatry. 2019;9:757. 9. Siskind D, Siskind V, Kisely S. Clozapine response rates among people with treatment-resistant schizophrenia: data from a systematic review and meta-analysis. Can J Psychiatry. 2017;62(11):772-777. 10. Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2009;109(1-3):10-14. 11. Nasrallah HA, Fedora R, Morton R. Successful treatment of clozapine-nonresponsive refractory hallucinations and delusions with pimavanserin, a serotonin 5HT-2A receptor inverse agonist. Schizophr Res. 2019;208:217-220. 12. Linden N, Onwuanibe A, Sandson N. Rapid resolution of psychotic symptoms in a patient with schizophrenia using allopurinol as an adjuvant: a case report. Clin Schizophr Relat Psychoses. 2014;7(4):231-234. 13 Lintunen J, Lähteenvuo M, Tiihonen J, et al. Adenosine modulators and calcium channel blockers as add-on treatment for schizophrenia. NPJ Schizophr. 2021;7(1):1. 14. Kulkarni J, Butler S, Riecher-Rössler A. Estrogens and SERMS as adjunctive treatments for schizophrenia. Front Neuroendocrinol. 2019;53:100743. doi: 10.1016/j.yfrne.2019.03.002 15. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, “just the facts” 5. Treatment and prevention. Past, present and future. Schizophr Res. 2010;122(1-3):1-23. 16. Nasrallah HA. Biomarkers in neuropsychiatric disorders: translating research to clinical applications. Biomarkers in Neuropsychiatry. 2019;1:100001. doi: 10.1016/j.bionps.2019.100001 17. Nasrallah HA. The dawn of precision psychiatry. Current Psychiatry. 2017;16(12):7-8,11.
For millennia, serious psychiatric brain disorders (aka mental illnesses, melancholia, madness, insanity) were written off as incurable, permanent afflictions. It’s no wonder that they were engulfed with the stigma of hopelessness.
But then came the era of serendipitous discoveries in the mid-20th century, with the felicitous arrival of antipsychotics, antidepressants, and lithium. The dogma of untreatability was shattered, but in its wake, the notion of treatment resistance emerged, and promptly became the bane of psychiatric clinicians and the practice of psychopharmacology.
Many patients with mood and psychotic disorders responded to the medications that were introduced in the 1950s and 1960s, but some either derived partial benefit or did not improve at all. These partial or poor responders were labeled “treatment-resistant,” and caring for them became a major challenge for psychiatric physicians that continues to this day. However, rapid advances in understanding the many etiologies and subtypes of the heterogeneous mood and psychotic disorders are invalidating the notion of treatment resistance, showing it is a fallacy and a misnomer. Let’s examine why.
Treatment-resistant depression (TRD)
Psychiatric clinics and hospitals are clogged with patients who do not respond to ≥2 evidence-based antidepressants and carry the disparaging label of “TRD.” But a patient manifesting what appears to be major depressive disorder (MDD) may actually have one of several types of depression that are unlikely to respond to an antidepressant, including:
iatrogenic depression due to a prescription medication
depression secondary to recreational drug use
depressive symptoms secondary to a general medical condition
bipolar depression.
Thus, a significant proportion of patients diagnosed with MDD are labeled TRD because they do not respond to standard antidepressants, when in fact they have been misdiagnosed and need a different treatment.
Even when the diagnosis of MDD is accurate, psychiatric neuroscience advances have informed us that MDD is a heterogeneous syndrome with multiple “biotypes” that share a similar phenotype.1,2 In the past, TRD has been defined as a failure to respond to ≥2 adequate trials (8 to 12 weeks at a maximum tolerated dose) of antidepressants from different classes (such as tricyclic or heterocyclic antidepressants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors). For decades, patients with TRD have been referred to electroconvulsive therapy (ECT), and have experienced an excellent response rate. So TRD is in fact an artificial concept and term, applied to a subtype of MDD that does not respond to standard antidepressants, but often responds very well to neurostimulation (ECT and transcranial magnetic stimulation [TMS]).
When an antidepressant is approved by the FDA based on “successful” placebo-controlled double-blind trials, there is always a subset of patients who do not respond. However, the success of a controlled clinical trial is based on a decline in overall mean depression rating scale score in the antidepressant group compared with the placebo group. Not a single antidepressant has ever exerted full efficacy in 100% of patients who received it in an FDA trial because the sample is always a heterogeneous mix of patients with various depression biotypes who meet the DSM clinical diagnosis of MDD. Most often, only approximately 50% do, which is enough to be statistically significantly better than the roughly 30% response rate in the placebo group. It is impossible for a heterogeneous syndrome comprised of biologically different “diseases” to respond to any single medication! Patients who do not respond to an antidepressant medication that works in other patients represent a different subtype of depression that is not TRD. Biotypes of the depression syndrome have different neurochemical underpinnings and may respond to different mechanisms of therapeutic action, yet to be discovered.
Continue to: A very common...
A very common clinical mistake occurs when patients with bipolar depression are misdiagnosed as having MDD because most of them experience depression as their initial mood episode. These patients often end up being classified as having TRD because bipolar depression very frequently fails to respond to several of the antidepressants that are FDA-approved for MDD. When these patients are correctly diagnosed, many will respond to one of the medications specifically approved for bipolar depression that were launched over the past 15 years (quetiapine, lurasidone, and cariprazine). However, bipolar disorder is also a heterogeneous spectrum, and some patients with bipolar depression may fail to respond to any of these 3 medications and are promptly regarded as TRD. Such patients often respond to neuromodulation (TMS, ECT, or vagus nerve stimulation [VNS]), indicating that they may have a different type of bipolar depression, such as bipolar type II.
A more recent example of the falsehood of TRD as a spurious diagnosis is the dramatic and rapid response of patients who are chronically depressed (both those with MDD and those with bipolar depression) to ketamine infusions.3,4 Responders to ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, prove that nonresponders to monoamine reuptake inhibitors must not be falsely labeled as having TRD. They have a different subtype within the depression syndrome that is mediated by glutamatergic pathways, instead of monoamines such as serotonin, norepinephrine, or dopamine. In addition, unlike monoaminergic antidepressants, NMDA antagonists rapidly reverse suicidal urges, above and beyond rapidly reversing chronic, so-called TRD.
In the same vein, numerous reports have shown that buprenorphine has significant efficacy in TRD (and suicide urges, as does ketamine), which implicates opioid pathways as mediating some subtypes of TRD.5 The monoamine model of depression, which dominated the field and dragged on for half a century, has distracted psychiatric researchers from exploring and recognizing the multiple neurochemical and neuroplastic pathways of the depression syndrome, thus falsely assuming that depression is a monolithic disorder that responds to elevating the activity of brain monoamines. This major blind spot led to the ersatz concept of TRD.
Treatment-resistant schizophrenia (TRS)
Since the discovery of chlorpromazine and other antipsychotics in the 1950s, it became apparent that a subset of patients with schizophrenia do not respond to medications that block dopamine D2 receptors. Partial responders were labeled as having TRS, and complete nonresponse was called refractory schizophrenia. Many patients with severe and persistent delusions and hallucinations were permanently hospitalized, and unable to live in the community like those who responded to dopamine antagonism.
In the late 1980s, the discovery that clozapine has significant efficacy in TRS and refractory schizophrenia provided the first insight that TRS and refractory schizophrenia represent different neurobiologic subtypes of schizophrenia.6,7 The extensive heterogeneity of schizophrenia (with hundreds of genetic and nongenetic etiologies) is now widely accepted.8 Patients with schizophrenia who do not respond to dopamine receptor antagonism should not be labeled TRS, because they can respond to a different antipsychotic agent, such as clozapine, which is believed to exert its efficacy via glutamate pathways.
Continue to: But what about the 50%...
But what about the 50% of patients with TRS or refractory schizophrenia who do not respond to clozapine?9 They do not have TRS, either, but represent different schizophrenia biotypes that may respond to other medications with different mechanisms of action, such as lamotrigine,10 which is a glutamate modulator; pimavanserin,11 which is an inverse agonist of the serotonin 5HT-2A receptor; allopurinol,12,13 an adenosine modulator; or estrogen,14 a neurosteroid. Future research will continue to unravel the many biotypes of the highly heterogeneous schizophrenia syndrome that are “nondopaminergic” and do not respond to the standard class of dopamine antagonists (previously called neuroleptics and now known as antipsychotics).15 Future treatments for schizophrenia may depart from modulating various neurotransmitter receptors to targeting entirely different neurobiologic processes, such as correcting mitochondria pathology, inhibiting microglia activation, repairing white matter, reversing apoptosis pathways, inducing neuroplasticity, arresting oxidative stress and inflammation, and other neuroprotective mechanisms.
The rapid growth of biomarkers in psychiatry16 will usher in an era of precision psychiatry17 that will eliminate the term “treatment resistance.” Our psychiatric practice will then benefit from “canceling” this demoralizing and clinically unjustified term that has needlessly fostered therapeutic nihilism among psychiatric physicians.
For millennia, serious psychiatric brain disorders (aka mental illnesses, melancholia, madness, insanity) were written off as incurable, permanent afflictions. It’s no wonder that they were engulfed with the stigma of hopelessness.
But then came the era of serendipitous discoveries in the mid-20th century, with the felicitous arrival of antipsychotics, antidepressants, and lithium. The dogma of untreatability was shattered, but in its wake, the notion of treatment resistance emerged, and promptly became the bane of psychiatric clinicians and the practice of psychopharmacology.
Many patients with mood and psychotic disorders responded to the medications that were introduced in the 1950s and 1960s, but some either derived partial benefit or did not improve at all. These partial or poor responders were labeled “treatment-resistant,” and caring for them became a major challenge for psychiatric physicians that continues to this day. However, rapid advances in understanding the many etiologies and subtypes of the heterogeneous mood and psychotic disorders are invalidating the notion of treatment resistance, showing it is a fallacy and a misnomer. Let’s examine why.
Treatment-resistant depression (TRD)
Psychiatric clinics and hospitals are clogged with patients who do not respond to ≥2 evidence-based antidepressants and carry the disparaging label of “TRD.” But a patient manifesting what appears to be major depressive disorder (MDD) may actually have one of several types of depression that are unlikely to respond to an antidepressant, including:
iatrogenic depression due to a prescription medication
depression secondary to recreational drug use
depressive symptoms secondary to a general medical condition
bipolar depression.
Thus, a significant proportion of patients diagnosed with MDD are labeled TRD because they do not respond to standard antidepressants, when in fact they have been misdiagnosed and need a different treatment.
Even when the diagnosis of MDD is accurate, psychiatric neuroscience advances have informed us that MDD is a heterogeneous syndrome with multiple “biotypes” that share a similar phenotype.1,2 In the past, TRD has been defined as a failure to respond to ≥2 adequate trials (8 to 12 weeks at a maximum tolerated dose) of antidepressants from different classes (such as tricyclic or heterocyclic antidepressants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors). For decades, patients with TRD have been referred to electroconvulsive therapy (ECT), and have experienced an excellent response rate. So TRD is in fact an artificial concept and term, applied to a subtype of MDD that does not respond to standard antidepressants, but often responds very well to neurostimulation (ECT and transcranial magnetic stimulation [TMS]).
When an antidepressant is approved by the FDA based on “successful” placebo-controlled double-blind trials, there is always a subset of patients who do not respond. However, the success of a controlled clinical trial is based on a decline in overall mean depression rating scale score in the antidepressant group compared with the placebo group. Not a single antidepressant has ever exerted full efficacy in 100% of patients who received it in an FDA trial because the sample is always a heterogeneous mix of patients with various depression biotypes who meet the DSM clinical diagnosis of MDD. Most often, only approximately 50% do, which is enough to be statistically significantly better than the roughly 30% response rate in the placebo group. It is impossible for a heterogeneous syndrome comprised of biologically different “diseases” to respond to any single medication! Patients who do not respond to an antidepressant medication that works in other patients represent a different subtype of depression that is not TRD. Biotypes of the depression syndrome have different neurochemical underpinnings and may respond to different mechanisms of therapeutic action, yet to be discovered.
Continue to: A very common...
A very common clinical mistake occurs when patients with bipolar depression are misdiagnosed as having MDD because most of them experience depression as their initial mood episode. These patients often end up being classified as having TRD because bipolar depression very frequently fails to respond to several of the antidepressants that are FDA-approved for MDD. When these patients are correctly diagnosed, many will respond to one of the medications specifically approved for bipolar depression that were launched over the past 15 years (quetiapine, lurasidone, and cariprazine). However, bipolar disorder is also a heterogeneous spectrum, and some patients with bipolar depression may fail to respond to any of these 3 medications and are promptly regarded as TRD. Such patients often respond to neuromodulation (TMS, ECT, or vagus nerve stimulation [VNS]), indicating that they may have a different type of bipolar depression, such as bipolar type II.
A more recent example of the falsehood of TRD as a spurious diagnosis is the dramatic and rapid response of patients who are chronically depressed (both those with MDD and those with bipolar depression) to ketamine infusions.3,4 Responders to ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, prove that nonresponders to monoamine reuptake inhibitors must not be falsely labeled as having TRD. They have a different subtype within the depression syndrome that is mediated by glutamatergic pathways, instead of monoamines such as serotonin, norepinephrine, or dopamine. In addition, unlike monoaminergic antidepressants, NMDA antagonists rapidly reverse suicidal urges, above and beyond rapidly reversing chronic, so-called TRD.
In the same vein, numerous reports have shown that buprenorphine has significant efficacy in TRD (and suicide urges, as does ketamine), which implicates opioid pathways as mediating some subtypes of TRD.5 The monoamine model of depression, which dominated the field and dragged on for half a century, has distracted psychiatric researchers from exploring and recognizing the multiple neurochemical and neuroplastic pathways of the depression syndrome, thus falsely assuming that depression is a monolithic disorder that responds to elevating the activity of brain monoamines. This major blind spot led to the ersatz concept of TRD.
Treatment-resistant schizophrenia (TRS)
Since the discovery of chlorpromazine and other antipsychotics in the 1950s, it became apparent that a subset of patients with schizophrenia do not respond to medications that block dopamine D2 receptors. Partial responders were labeled as having TRS, and complete nonresponse was called refractory schizophrenia. Many patients with severe and persistent delusions and hallucinations were permanently hospitalized, and unable to live in the community like those who responded to dopamine antagonism.
In the late 1980s, the discovery that clozapine has significant efficacy in TRS and refractory schizophrenia provided the first insight that TRS and refractory schizophrenia represent different neurobiologic subtypes of schizophrenia.6,7 The extensive heterogeneity of schizophrenia (with hundreds of genetic and nongenetic etiologies) is now widely accepted.8 Patients with schizophrenia who do not respond to dopamine receptor antagonism should not be labeled TRS, because they can respond to a different antipsychotic agent, such as clozapine, which is believed to exert its efficacy via glutamate pathways.
Continue to: But what about the 50%...
But what about the 50% of patients with TRS or refractory schizophrenia who do not respond to clozapine?9 They do not have TRS, either, but represent different schizophrenia biotypes that may respond to other medications with different mechanisms of action, such as lamotrigine,10 which is a glutamate modulator; pimavanserin,11 which is an inverse agonist of the serotonin 5HT-2A receptor; allopurinol,12,13 an adenosine modulator; or estrogen,14 a neurosteroid. Future research will continue to unravel the many biotypes of the highly heterogeneous schizophrenia syndrome that are “nondopaminergic” and do not respond to the standard class of dopamine antagonists (previously called neuroleptics and now known as antipsychotics).15 Future treatments for schizophrenia may depart from modulating various neurotransmitter receptors to targeting entirely different neurobiologic processes, such as correcting mitochondria pathology, inhibiting microglia activation, repairing white matter, reversing apoptosis pathways, inducing neuroplasticity, arresting oxidative stress and inflammation, and other neuroprotective mechanisms.
The rapid growth of biomarkers in psychiatry16 will usher in an era of precision psychiatry17 that will eliminate the term “treatment resistance.” Our psychiatric practice will then benefit from “canceling” this demoralizing and clinically unjustified term that has needlessly fostered therapeutic nihilism among psychiatric physicians.
References
1. Milaneschi Y, Lamers F, Berk M, et al. Depression heterogeneity and its biological underpinnings: toward immunometabolism depression. Biol Psychiatry. 2020;88(5):369-380. 2. Akiskal HS, McKinney WT Jr. Overview of recent research in depression. Integration of ten conceptual models into a comprehensive clinical frame. Arch Gen Psychiatry. 1975;32(3):285-305. 3. Zarate CA Jr. Ketamine: a new chapter in antidepressant development. Brazilian J Psychiatry. 2020;42(6):581-582. 4. Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67(8):793-802. 5. Serafini G, Adavastro G, Canepa G, et al. The efficacy of buprenorphine in major depression, treatment-resistant depression and suicidal behavior: a systematic review. Int J Mol Sci. 2018;19(8):2410. 6. Potkin SG, Kane JM, Correll CU, et al. The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research. NPJ Schizophr. 2020;6(1):1. 7. Campana M, Falkai P, Siskind D, et al. Characteristics and definitions of ultra-treatment-resistant schizophrenia - a systematic review and meta-analysis. Schizophr Res. 2021;228:218-226. 8. Kinon BJ. The group of treatment resistant schizophrenias. Heterogeneity in treatment-resistant schizophrenia (TRS). Front Psychiatry. 2019;9:757. 9. Siskind D, Siskind V, Kisely S. Clozapine response rates among people with treatment-resistant schizophrenia: data from a systematic review and meta-analysis. Can J Psychiatry. 2017;62(11):772-777. 10. Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2009;109(1-3):10-14. 11. Nasrallah HA, Fedora R, Morton R. Successful treatment of clozapine-nonresponsive refractory hallucinations and delusions with pimavanserin, a serotonin 5HT-2A receptor inverse agonist. Schizophr Res. 2019;208:217-220. 12. Linden N, Onwuanibe A, Sandson N. Rapid resolution of psychotic symptoms in a patient with schizophrenia using allopurinol as an adjuvant: a case report. Clin Schizophr Relat Psychoses. 2014;7(4):231-234. 13 Lintunen J, Lähteenvuo M, Tiihonen J, et al. Adenosine modulators and calcium channel blockers as add-on treatment for schizophrenia. NPJ Schizophr. 2021;7(1):1. 14. Kulkarni J, Butler S, Riecher-Rössler A. Estrogens and SERMS as adjunctive treatments for schizophrenia. Front Neuroendocrinol. 2019;53:100743. doi: 10.1016/j.yfrne.2019.03.002 15. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, “just the facts” 5. Treatment and prevention. Past, present and future. Schizophr Res. 2010;122(1-3):1-23. 16. Nasrallah HA. Biomarkers in neuropsychiatric disorders: translating research to clinical applications. Biomarkers in Neuropsychiatry. 2019;1:100001. doi: 10.1016/j.bionps.2019.100001 17. Nasrallah HA. The dawn of precision psychiatry. Current Psychiatry. 2017;16(12):7-8,11.
References
1. Milaneschi Y, Lamers F, Berk M, et al. Depression heterogeneity and its biological underpinnings: toward immunometabolism depression. Biol Psychiatry. 2020;88(5):369-380. 2. Akiskal HS, McKinney WT Jr. Overview of recent research in depression. Integration of ten conceptual models into a comprehensive clinical frame. Arch Gen Psychiatry. 1975;32(3):285-305. 3. Zarate CA Jr. Ketamine: a new chapter in antidepressant development. Brazilian J Psychiatry. 2020;42(6):581-582. 4. Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67(8):793-802. 5. Serafini G, Adavastro G, Canepa G, et al. The efficacy of buprenorphine in major depression, treatment-resistant depression and suicidal behavior: a systematic review. Int J Mol Sci. 2018;19(8):2410. 6. Potkin SG, Kane JM, Correll CU, et al. The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research. NPJ Schizophr. 2020;6(1):1. 7. Campana M, Falkai P, Siskind D, et al. Characteristics and definitions of ultra-treatment-resistant schizophrenia - a systematic review and meta-analysis. Schizophr Res. 2021;228:218-226. 8. Kinon BJ. The group of treatment resistant schizophrenias. Heterogeneity in treatment-resistant schizophrenia (TRS). Front Psychiatry. 2019;9:757. 9. Siskind D, Siskind V, Kisely S. Clozapine response rates among people with treatment-resistant schizophrenia: data from a systematic review and meta-analysis. Can J Psychiatry. 2017;62(11):772-777. 10. Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2009;109(1-3):10-14. 11. Nasrallah HA, Fedora R, Morton R. Successful treatment of clozapine-nonresponsive refractory hallucinations and delusions with pimavanserin, a serotonin 5HT-2A receptor inverse agonist. Schizophr Res. 2019;208:217-220. 12. Linden N, Onwuanibe A, Sandson N. Rapid resolution of psychotic symptoms in a patient with schizophrenia using allopurinol as an adjuvant: a case report. Clin Schizophr Relat Psychoses. 2014;7(4):231-234. 13 Lintunen J, Lähteenvuo M, Tiihonen J, et al. Adenosine modulators and calcium channel blockers as add-on treatment for schizophrenia. NPJ Schizophr. 2021;7(1):1. 14. Kulkarni J, Butler S, Riecher-Rössler A. Estrogens and SERMS as adjunctive treatments for schizophrenia. Front Neuroendocrinol. 2019;53:100743. doi: 10.1016/j.yfrne.2019.03.002 15. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, “just the facts” 5. Treatment and prevention. Past, present and future. Schizophr Res. 2010;122(1-3):1-23. 16. Nasrallah HA. Biomarkers in neuropsychiatric disorders: translating research to clinical applications. Biomarkers in Neuropsychiatry. 2019;1:100001. doi: 10.1016/j.bionps.2019.100001 17. Nasrallah HA. The dawn of precision psychiatry. Current Psychiatry. 2017;16(12):7-8,11.
Posttraumatic stress disorder may occur in up to a third of patients who recover from severe COVID-19 infection, new research suggests.
A study of more than 300 patients who presented to the emergency department with the virus showed a 30.2% prevalence for PTSD 30-120 days after COVID recovery.
Factors linked to higher rates of PTSD included experiencing delirium or agitation during the acute COVID phase or having persistent medical symptoms after hospitalization.
Additional diagnoses, such as depressive and hypomanic episodes and generalized anxiety disorder (GAD), were also present in some of the survivors.
“Previous coronavirus epidemics were associated with PTSD diagnoses in postillness stages, with meta-analytic findings indicating a prevalence of 32.2%,” write the investigators, led by Delfina Janiri, MD, department of psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome.
However, data focused specifically on COVID-19 have been “piecemeal,” they add.
The findings were published online Feb. 18 in a research letter in JAMA Psychiatry.
A traumatic event
From April to October 2020, the researchers assessed 381 consecutive patients (100% white; 56.4% men; mean age, 55.3 years) who presented to the ED and subsequently participated in a health check at the Fondazione Policlinico Universitario Agostino Gemelli.
The mean length of stay for the 309 patients hospitalized with severe COVID-19 was 18.4 days.
Results showed that 115 participants (30.2%) had PTSD, based on DSM-5 criteria, and 55.7% of the women had the disorder. Additional diagnoses found in the full patient population included:
Depressive episodes (17.3%).
GAD (7%).
Hypomanic episodes (0.7%).
Psychotic disorders (0.2%).
Patients with PTSD had higher rates than those without PTSD of a previous history of psychiatric disorders (34.8% vs. 20.7%; P = .003) and of delirium or agitation during hospitalization, as assessed with the Confusion Assessment Method (16.5% vs. 6.4%; P = .002).
In addition, 62.6% of those with PTSD had three or more persistent COVID-19 symptoms vs. 37.2% of their counterparts without PTSD (P < .001).
After logistic regression analyses, significant factors associated with a PTSD diagnosis were persistent medical symptoms (P = .002), delirium or agitation (P = .02), and being female (P = .02).
The investigators note that their results are “in line” with findings reported in research examining other traumatic events. This includes about 30% of Hurricane Katrina survivors who experienced PTSD, as did around 25% of survivors of the 2011 “Great Japan Earthquake and Tsunami.”
Study limitations cited include the “relatively small” size of the patient population, that it focused on only one participating center, and that it didn’t include a control group of non-COVID patients who reported to the ED.
“Further longitudinal studies are needed to tailor therapeutic interventions and prevention strategies,” the researchers write.
Dr. Janiri and four of the five other authors have disclosed no relevant financial relationships. The other author, Gabriele Sani, MD, reported having received personal fees from Angelini Spa, Janssen, and Lundbeck outside the submitted work.
A version of this article first appeared on Medscape.com.
Posttraumatic stress disorder may occur in up to a third of patients who recover from severe COVID-19 infection, new research suggests.
A study of more than 300 patients who presented to the emergency department with the virus showed a 30.2% prevalence for PTSD 30-120 days after COVID recovery.
Factors linked to higher rates of PTSD included experiencing delirium or agitation during the acute COVID phase or having persistent medical symptoms after hospitalization.
Additional diagnoses, such as depressive and hypomanic episodes and generalized anxiety disorder (GAD), were also present in some of the survivors.
“Previous coronavirus epidemics were associated with PTSD diagnoses in postillness stages, with meta-analytic findings indicating a prevalence of 32.2%,” write the investigators, led by Delfina Janiri, MD, department of psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome.
However, data focused specifically on COVID-19 have been “piecemeal,” they add.
The findings were published online Feb. 18 in a research letter in JAMA Psychiatry.
A traumatic event
From April to October 2020, the researchers assessed 381 consecutive patients (100% white; 56.4% men; mean age, 55.3 years) who presented to the ED and subsequently participated in a health check at the Fondazione Policlinico Universitario Agostino Gemelli.
The mean length of stay for the 309 patients hospitalized with severe COVID-19 was 18.4 days.
Results showed that 115 participants (30.2%) had PTSD, based on DSM-5 criteria, and 55.7% of the women had the disorder. Additional diagnoses found in the full patient population included:
Depressive episodes (17.3%).
GAD (7%).
Hypomanic episodes (0.7%).
Psychotic disorders (0.2%).
Patients with PTSD had higher rates than those without PTSD of a previous history of psychiatric disorders (34.8% vs. 20.7%; P = .003) and of delirium or agitation during hospitalization, as assessed with the Confusion Assessment Method (16.5% vs. 6.4%; P = .002).
In addition, 62.6% of those with PTSD had three or more persistent COVID-19 symptoms vs. 37.2% of their counterparts without PTSD (P < .001).
After logistic regression analyses, significant factors associated with a PTSD diagnosis were persistent medical symptoms (P = .002), delirium or agitation (P = .02), and being female (P = .02).
The investigators note that their results are “in line” with findings reported in research examining other traumatic events. This includes about 30% of Hurricane Katrina survivors who experienced PTSD, as did around 25% of survivors of the 2011 “Great Japan Earthquake and Tsunami.”
Study limitations cited include the “relatively small” size of the patient population, that it focused on only one participating center, and that it didn’t include a control group of non-COVID patients who reported to the ED.
“Further longitudinal studies are needed to tailor therapeutic interventions and prevention strategies,” the researchers write.
Dr. Janiri and four of the five other authors have disclosed no relevant financial relationships. The other author, Gabriele Sani, MD, reported having received personal fees from Angelini Spa, Janssen, and Lundbeck outside the submitted work.
A version of this article first appeared on Medscape.com.
Posttraumatic stress disorder may occur in up to a third of patients who recover from severe COVID-19 infection, new research suggests.
A study of more than 300 patients who presented to the emergency department with the virus showed a 30.2% prevalence for PTSD 30-120 days after COVID recovery.
Factors linked to higher rates of PTSD included experiencing delirium or agitation during the acute COVID phase or having persistent medical symptoms after hospitalization.
Additional diagnoses, such as depressive and hypomanic episodes and generalized anxiety disorder (GAD), were also present in some of the survivors.
“Previous coronavirus epidemics were associated with PTSD diagnoses in postillness stages, with meta-analytic findings indicating a prevalence of 32.2%,” write the investigators, led by Delfina Janiri, MD, department of psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome.
However, data focused specifically on COVID-19 have been “piecemeal,” they add.
The findings were published online Feb. 18 in a research letter in JAMA Psychiatry.
A traumatic event
From April to October 2020, the researchers assessed 381 consecutive patients (100% white; 56.4% men; mean age, 55.3 years) who presented to the ED and subsequently participated in a health check at the Fondazione Policlinico Universitario Agostino Gemelli.
The mean length of stay for the 309 patients hospitalized with severe COVID-19 was 18.4 days.
Results showed that 115 participants (30.2%) had PTSD, based on DSM-5 criteria, and 55.7% of the women had the disorder. Additional diagnoses found in the full patient population included:
Depressive episodes (17.3%).
GAD (7%).
Hypomanic episodes (0.7%).
Psychotic disorders (0.2%).
Patients with PTSD had higher rates than those without PTSD of a previous history of psychiatric disorders (34.8% vs. 20.7%; P = .003) and of delirium or agitation during hospitalization, as assessed with the Confusion Assessment Method (16.5% vs. 6.4%; P = .002).
In addition, 62.6% of those with PTSD had three or more persistent COVID-19 symptoms vs. 37.2% of their counterparts without PTSD (P < .001).
After logistic regression analyses, significant factors associated with a PTSD diagnosis were persistent medical symptoms (P = .002), delirium or agitation (P = .02), and being female (P = .02).
The investigators note that their results are “in line” with findings reported in research examining other traumatic events. This includes about 30% of Hurricane Katrina survivors who experienced PTSD, as did around 25% of survivors of the 2011 “Great Japan Earthquake and Tsunami.”
Study limitations cited include the “relatively small” size of the patient population, that it focused on only one participating center, and that it didn’t include a control group of non-COVID patients who reported to the ED.
“Further longitudinal studies are needed to tailor therapeutic interventions and prevention strategies,” the researchers write.
Dr. Janiri and four of the five other authors have disclosed no relevant financial relationships. The other author, Gabriele Sani, MD, reported having received personal fees from Angelini Spa, Janssen, and Lundbeck outside the submitted work.
A version of this article first appeared on Medscape.com.
Researchers have come a long way in understanding the link between acute inflammation and treatment-resistant depression, but more work needs to be done, according to Mark Hyman Rapaport, MD.
Svisio/Thinkstock
“Inflammation has been a hot topic in the past decade, both because of its impact in medical disorders and in psychiatric disorders,” Dr. Rapaport, CEO of the Huntsman Mental Health Institute in Salt Lake City, Utah, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “We run into difficulty with chronic inflammation, which we see with rheumatic disorders, and when we think of metabolic syndrome and obesity.”
The immune system helps to control energy regulation and neuroendocrine function in acute inflammation and chronic inflammatory diseases. “We see a variety of effects on the central nervous system or liver function or on homeostasis of the body,” said Dr. Rapaport, who also chairs the department of psychiatry at the University of Utah, also in Salt Lake City. “These are all normal and necessary to channel energy to the immune system in order to fight what’s necessary in acute inflammatory response.”
A chronic state of inflammation can result in prolonged allocation of fuels to the immune system, tissue inflammation, and a chronically aberrant immune reaction, he continued. This can cause depressive symptoms/fatigue, anorexia, malnutrition, muscle wasting, cachectic obesity, insulin resistance, dyslipidemia, increased adipose tissue in the proximity of inflammatory lesion, alterations of steroid hormone axes, elevated sympathetic tone, hypertension, decreased parasympathetic tone, inflammation-related anemia, and osteopenia. “So, chronic inflammation has a lot of long-term sequelae that are detrimental,” he said.
Both physical stress and psychological stress also cause an inflammatory state. After looking at the medical literature, Dr. Rapaport and colleagues began to wonder whether inflammation and immune activation associated with psychiatric disorders are attributable to the stress of acute illness. To find out, they performed a meta-analysis of blood cytokine network alterations in psychiatric patients and evaluated comparisons between schizophrenia, bipolar disorder, and depression. A total of three meta-analyses were performed: one of acute/inpatient studies, one on the impact of acute treatment, and one of outpatient studies. The researchers hypothesized that inflammatory and immune findings in psychiatric illnesses were tied to two distinct etiologies: the acute stress of illness and intrinsic immune dysfunction.
The meta-analyses included 68 studies: 40 involving patients with schizophrenia, 18 involving those with major depressive disorder (MDD) and 10 involving those with bipolar disorder. The researchers found that levels of four cytokines were significantly increased in acutely ill patients with schizophrenia, bipolar mania, and MDD, compared with controls: interleukin-6, tumor necrosis factor–alpha (TNF-alpha), soluble IL-2 receptor (sIL-2R), and IL-1 receptor antagonist (IL-1RA). “There has not been a consistent blood panel used across studies, be it within a disorder itself like depression, or across disorders,” Dr. Rapaport noted. “This is a challenge that we face in looking at these data.”
Following treatment of acute illness, IL-6 levels significantly decreased in schizophrenia and MDD, but no significant changes in TNF-alpha levels were observed in patients with schizophrenia or MDD. In addition, sIL-2R levels increase in schizophrenia but remained unchanged in bipolar and MDD, while IL-1RA levels in bipolar mania decreased but remained unchanged in MDD. Meanwhile, assessment of the study’s 24 outpatient studies revealed that levels of IL-6 were significantly increased in outpatients with schizophrenia, euthymic bipolar disorder, and MDD, compared with controls (P < .01 for each). In addition, levels of IL-1 beta and sIL-2R were significantly increased in outpatients with schizophrenia and bipolar disorder.
According to Dr. Rapaport, these meta-analyses suggest that there are likely inflammatory immune findings present in acutely ill patients with MDD, schizophrenia, and bipolar disorder.
“Some of this activation decreases with effective acute treatment of the disorder,” he said. “The data suggest that immune changes are present in a subset of patients with all three disorders.”
Advancing this area of research requires a better understanding of the bidirectional interactions between the brain and periphery. “We also need to understand the regulatory role that microglia and astroglia play within the brain,” he said. “We need to identify changes in brain circuitry and function associated with inflammation and other immune changes. We also need to carefully scrutinize publications, understand the assumptions behind the statistics, and carry out more research beyond the protein level.”
He concluded his presentation by calling for research to help clinicians differentiate acute from chronic inflammation. “The study of both is important,” he said. “We need to understand the pathophysiology of immune changes in psychiatric disorders. We need to study both the triggers and pathways to resolution.”
Dr. Rapaport disclosed that he has received research support from the National Institutes of Health, the National Institute of Mental Health, and the National Center for Complementary and Integrative Health.
Researchers have come a long way in understanding the link between acute inflammation and treatment-resistant depression, but more work needs to be done, according to Mark Hyman Rapaport, MD.
Svisio/Thinkstock
“Inflammation has been a hot topic in the past decade, both because of its impact in medical disorders and in psychiatric disorders,” Dr. Rapaport, CEO of the Huntsman Mental Health Institute in Salt Lake City, Utah, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “We run into difficulty with chronic inflammation, which we see with rheumatic disorders, and when we think of metabolic syndrome and obesity.”
The immune system helps to control energy regulation and neuroendocrine function in acute inflammation and chronic inflammatory diseases. “We see a variety of effects on the central nervous system or liver function or on homeostasis of the body,” said Dr. Rapaport, who also chairs the department of psychiatry at the University of Utah, also in Salt Lake City. “These are all normal and necessary to channel energy to the immune system in order to fight what’s necessary in acute inflammatory response.”
A chronic state of inflammation can result in prolonged allocation of fuels to the immune system, tissue inflammation, and a chronically aberrant immune reaction, he continued. This can cause depressive symptoms/fatigue, anorexia, malnutrition, muscle wasting, cachectic obesity, insulin resistance, dyslipidemia, increased adipose tissue in the proximity of inflammatory lesion, alterations of steroid hormone axes, elevated sympathetic tone, hypertension, decreased parasympathetic tone, inflammation-related anemia, and osteopenia. “So, chronic inflammation has a lot of long-term sequelae that are detrimental,” he said.
Both physical stress and psychological stress also cause an inflammatory state. After looking at the medical literature, Dr. Rapaport and colleagues began to wonder whether inflammation and immune activation associated with psychiatric disorders are attributable to the stress of acute illness. To find out, they performed a meta-analysis of blood cytokine network alterations in psychiatric patients and evaluated comparisons between schizophrenia, bipolar disorder, and depression. A total of three meta-analyses were performed: one of acute/inpatient studies, one on the impact of acute treatment, and one of outpatient studies. The researchers hypothesized that inflammatory and immune findings in psychiatric illnesses were tied to two distinct etiologies: the acute stress of illness and intrinsic immune dysfunction.
The meta-analyses included 68 studies: 40 involving patients with schizophrenia, 18 involving those with major depressive disorder (MDD) and 10 involving those with bipolar disorder. The researchers found that levels of four cytokines were significantly increased in acutely ill patients with schizophrenia, bipolar mania, and MDD, compared with controls: interleukin-6, tumor necrosis factor–alpha (TNF-alpha), soluble IL-2 receptor (sIL-2R), and IL-1 receptor antagonist (IL-1RA). “There has not been a consistent blood panel used across studies, be it within a disorder itself like depression, or across disorders,” Dr. Rapaport noted. “This is a challenge that we face in looking at these data.”
Following treatment of acute illness, IL-6 levels significantly decreased in schizophrenia and MDD, but no significant changes in TNF-alpha levels were observed in patients with schizophrenia or MDD. In addition, sIL-2R levels increase in schizophrenia but remained unchanged in bipolar and MDD, while IL-1RA levels in bipolar mania decreased but remained unchanged in MDD. Meanwhile, assessment of the study’s 24 outpatient studies revealed that levels of IL-6 were significantly increased in outpatients with schizophrenia, euthymic bipolar disorder, and MDD, compared with controls (P < .01 for each). In addition, levels of IL-1 beta and sIL-2R were significantly increased in outpatients with schizophrenia and bipolar disorder.
According to Dr. Rapaport, these meta-analyses suggest that there are likely inflammatory immune findings present in acutely ill patients with MDD, schizophrenia, and bipolar disorder.
“Some of this activation decreases with effective acute treatment of the disorder,” he said. “The data suggest that immune changes are present in a subset of patients with all three disorders.”
Advancing this area of research requires a better understanding of the bidirectional interactions between the brain and periphery. “We also need to understand the regulatory role that microglia and astroglia play within the brain,” he said. “We need to identify changes in brain circuitry and function associated with inflammation and other immune changes. We also need to carefully scrutinize publications, understand the assumptions behind the statistics, and carry out more research beyond the protein level.”
He concluded his presentation by calling for research to help clinicians differentiate acute from chronic inflammation. “The study of both is important,” he said. “We need to understand the pathophysiology of immune changes in psychiatric disorders. We need to study both the triggers and pathways to resolution.”
Dr. Rapaport disclosed that he has received research support from the National Institutes of Health, the National Institute of Mental Health, and the National Center for Complementary and Integrative Health.
Researchers have come a long way in understanding the link between acute inflammation and treatment-resistant depression, but more work needs to be done, according to Mark Hyman Rapaport, MD.
Svisio/Thinkstock
“Inflammation has been a hot topic in the past decade, both because of its impact in medical disorders and in psychiatric disorders,” Dr. Rapaport, CEO of the Huntsman Mental Health Institute in Salt Lake City, Utah, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “We run into difficulty with chronic inflammation, which we see with rheumatic disorders, and when we think of metabolic syndrome and obesity.”
The immune system helps to control energy regulation and neuroendocrine function in acute inflammation and chronic inflammatory diseases. “We see a variety of effects on the central nervous system or liver function or on homeostasis of the body,” said Dr. Rapaport, who also chairs the department of psychiatry at the University of Utah, also in Salt Lake City. “These are all normal and necessary to channel energy to the immune system in order to fight what’s necessary in acute inflammatory response.”
A chronic state of inflammation can result in prolonged allocation of fuels to the immune system, tissue inflammation, and a chronically aberrant immune reaction, he continued. This can cause depressive symptoms/fatigue, anorexia, malnutrition, muscle wasting, cachectic obesity, insulin resistance, dyslipidemia, increased adipose tissue in the proximity of inflammatory lesion, alterations of steroid hormone axes, elevated sympathetic tone, hypertension, decreased parasympathetic tone, inflammation-related anemia, and osteopenia. “So, chronic inflammation has a lot of long-term sequelae that are detrimental,” he said.
Both physical stress and psychological stress also cause an inflammatory state. After looking at the medical literature, Dr. Rapaport and colleagues began to wonder whether inflammation and immune activation associated with psychiatric disorders are attributable to the stress of acute illness. To find out, they performed a meta-analysis of blood cytokine network alterations in psychiatric patients and evaluated comparisons between schizophrenia, bipolar disorder, and depression. A total of three meta-analyses were performed: one of acute/inpatient studies, one on the impact of acute treatment, and one of outpatient studies. The researchers hypothesized that inflammatory and immune findings in psychiatric illnesses were tied to two distinct etiologies: the acute stress of illness and intrinsic immune dysfunction.
The meta-analyses included 68 studies: 40 involving patients with schizophrenia, 18 involving those with major depressive disorder (MDD) and 10 involving those with bipolar disorder. The researchers found that levels of four cytokines were significantly increased in acutely ill patients with schizophrenia, bipolar mania, and MDD, compared with controls: interleukin-6, tumor necrosis factor–alpha (TNF-alpha), soluble IL-2 receptor (sIL-2R), and IL-1 receptor antagonist (IL-1RA). “There has not been a consistent blood panel used across studies, be it within a disorder itself like depression, or across disorders,” Dr. Rapaport noted. “This is a challenge that we face in looking at these data.”
Following treatment of acute illness, IL-6 levels significantly decreased in schizophrenia and MDD, but no significant changes in TNF-alpha levels were observed in patients with schizophrenia or MDD. In addition, sIL-2R levels increase in schizophrenia but remained unchanged in bipolar and MDD, while IL-1RA levels in bipolar mania decreased but remained unchanged in MDD. Meanwhile, assessment of the study’s 24 outpatient studies revealed that levels of IL-6 were significantly increased in outpatients with schizophrenia, euthymic bipolar disorder, and MDD, compared with controls (P < .01 for each). In addition, levels of IL-1 beta and sIL-2R were significantly increased in outpatients with schizophrenia and bipolar disorder.
According to Dr. Rapaport, these meta-analyses suggest that there are likely inflammatory immune findings present in acutely ill patients with MDD, schizophrenia, and bipolar disorder.
“Some of this activation decreases with effective acute treatment of the disorder,” he said. “The data suggest that immune changes are present in a subset of patients with all three disorders.”
Advancing this area of research requires a better understanding of the bidirectional interactions between the brain and periphery. “We also need to understand the regulatory role that microglia and astroglia play within the brain,” he said. “We need to identify changes in brain circuitry and function associated with inflammation and other immune changes. We also need to carefully scrutinize publications, understand the assumptions behind the statistics, and carry out more research beyond the protein level.”
He concluded his presentation by calling for research to help clinicians differentiate acute from chronic inflammation. “The study of both is important,” he said. “We need to understand the pathophysiology of immune changes in psychiatric disorders. We need to study both the triggers and pathways to resolution.”
Dr. Rapaport disclosed that he has received research support from the National Institutes of Health, the National Institute of Mental Health, and the National Center for Complementary and Integrative Health.
Schizophrenia-related genes in the placenta are predictive of the size of a baby’s brain at birth and the rate of cognitive development. In a complicated pregnancy, such genes could raise the risk of developing schizophrenia later in life, new research suggests.
“This is further evidence that early life matters in schizophrenia, and the placenta plays a bigger role than we imagined,” Daniel R. Weinberger, MD, director and CEO, Lieber Institute for Brain Development, and professor of neurology, psychiatry, and neuroscience, Johns Hopkins University, Baltimore, said in a news release.
Dr. Daniel Weinberger
“The holy grail would be to identify, based by complicated pregnancies and placental risk scores, who is at maximum risk for schizophrenia from very early in life, and these individuals could be followed more carefully,” Dr. Weinberger said in an interview.
The study was published online Feb. 8 in Proceedings of the National Academy of Sciences.
A therapeutic target?
As reported by this news organization, in 2018, the same group of researchers reported that genes associated with schizophrenia are activated in the placenta during a complicated pregnancy, increasing a child’s risk of developing schizophrenia later in life.
In this latest study, they further explored the biological interplay between placental health and neurodevelopment.
They found that a higher placental genomic risk score for schizophrenia, in conjunction with early-life complications during pregnancy, at labor/delivery, and early in neonatal life, is associated with changes in early brain growth and function, particularly in males.
“The higher the placental schizophrenia gene risk score, the smaller the brain size at birth, and this was associated with slower cognitive development over the first 2 years of life – particularly in the first year of life,” said Dr. Weinberger.
This research defines a “potentially reversible neurodevelopmental path of risk that may be unique to schizophrenia,” the researchers write.
Although most individuals on this altered neurodevelopmental path likely “canalize” back toward normal development, some may not be rescued and instead “decanalize” toward illness, they add.
To date, prevention of schizophrenia from early life has seemed “unapproachable if not unimaginable, but these new insights offer possibilities to change the paradigm,” Dr. Weinberger said in the news release.
“Measuring schizophrenia genetic scores in the placenta combined with studying the first 2 years of cognitive developmental patterns and early life complications could prove to be an important approach to identify those babies with increased risks,” he added.
Important research
Commenting on the study for this news organization, Christopher A. Ross, MD, PhD, professor of psychiatry and behavioral sciences, Johns Hopkins Medicine, Baltimore, said that this is “an interesting and important paper that replicates and extends previous findings of the relationship of placenta genes to schizophrenia in adults.”
“The hypothesis continues to be – and they are continuing to support it – that events in early development could set a person up for a risk of schizophrenia later in life,” said Dr. Ross.
This research, he added, also supports the concept that there are at least two broad classes of genetic risk for schizophrenia.
“One acts through genes that are expressed in the brain and doesn’t relate to early life events, and the other acts through genes expressed in the placenta in patients with these early life events,” said Dr. Ross.
The study had no specific funding. Dr. Weinberger and Dr. Ross have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Schizophrenia-related genes in the placenta are predictive of the size of a baby’s brain at birth and the rate of cognitive development. In a complicated pregnancy, such genes could raise the risk of developing schizophrenia later in life, new research suggests.
“This is further evidence that early life matters in schizophrenia, and the placenta plays a bigger role than we imagined,” Daniel R. Weinberger, MD, director and CEO, Lieber Institute for Brain Development, and professor of neurology, psychiatry, and neuroscience, Johns Hopkins University, Baltimore, said in a news release.
Dr. Daniel Weinberger
“The holy grail would be to identify, based by complicated pregnancies and placental risk scores, who is at maximum risk for schizophrenia from very early in life, and these individuals could be followed more carefully,” Dr. Weinberger said in an interview.
The study was published online Feb. 8 in Proceedings of the National Academy of Sciences.
A therapeutic target?
As reported by this news organization, in 2018, the same group of researchers reported that genes associated with schizophrenia are activated in the placenta during a complicated pregnancy, increasing a child’s risk of developing schizophrenia later in life.
In this latest study, they further explored the biological interplay between placental health and neurodevelopment.
They found that a higher placental genomic risk score for schizophrenia, in conjunction with early-life complications during pregnancy, at labor/delivery, and early in neonatal life, is associated with changes in early brain growth and function, particularly in males.
“The higher the placental schizophrenia gene risk score, the smaller the brain size at birth, and this was associated with slower cognitive development over the first 2 years of life – particularly in the first year of life,” said Dr. Weinberger.
This research defines a “potentially reversible neurodevelopmental path of risk that may be unique to schizophrenia,” the researchers write.
Although most individuals on this altered neurodevelopmental path likely “canalize” back toward normal development, some may not be rescued and instead “decanalize” toward illness, they add.
To date, prevention of schizophrenia from early life has seemed “unapproachable if not unimaginable, but these new insights offer possibilities to change the paradigm,” Dr. Weinberger said in the news release.
“Measuring schizophrenia genetic scores in the placenta combined with studying the first 2 years of cognitive developmental patterns and early life complications could prove to be an important approach to identify those babies with increased risks,” he added.
Important research
Commenting on the study for this news organization, Christopher A. Ross, MD, PhD, professor of psychiatry and behavioral sciences, Johns Hopkins Medicine, Baltimore, said that this is “an interesting and important paper that replicates and extends previous findings of the relationship of placenta genes to schizophrenia in adults.”
“The hypothesis continues to be – and they are continuing to support it – that events in early development could set a person up for a risk of schizophrenia later in life,” said Dr. Ross.
This research, he added, also supports the concept that there are at least two broad classes of genetic risk for schizophrenia.
“One acts through genes that are expressed in the brain and doesn’t relate to early life events, and the other acts through genes expressed in the placenta in patients with these early life events,” said Dr. Ross.
The study had no specific funding. Dr. Weinberger and Dr. Ross have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Schizophrenia-related genes in the placenta are predictive of the size of a baby’s brain at birth and the rate of cognitive development. In a complicated pregnancy, such genes could raise the risk of developing schizophrenia later in life, new research suggests.
“This is further evidence that early life matters in schizophrenia, and the placenta plays a bigger role than we imagined,” Daniel R. Weinberger, MD, director and CEO, Lieber Institute for Brain Development, and professor of neurology, psychiatry, and neuroscience, Johns Hopkins University, Baltimore, said in a news release.
Dr. Daniel Weinberger
“The holy grail would be to identify, based by complicated pregnancies and placental risk scores, who is at maximum risk for schizophrenia from very early in life, and these individuals could be followed more carefully,” Dr. Weinberger said in an interview.
The study was published online Feb. 8 in Proceedings of the National Academy of Sciences.
A therapeutic target?
As reported by this news organization, in 2018, the same group of researchers reported that genes associated with schizophrenia are activated in the placenta during a complicated pregnancy, increasing a child’s risk of developing schizophrenia later in life.
In this latest study, they further explored the biological interplay between placental health and neurodevelopment.
They found that a higher placental genomic risk score for schizophrenia, in conjunction with early-life complications during pregnancy, at labor/delivery, and early in neonatal life, is associated with changes in early brain growth and function, particularly in males.
“The higher the placental schizophrenia gene risk score, the smaller the brain size at birth, and this was associated with slower cognitive development over the first 2 years of life – particularly in the first year of life,” said Dr. Weinberger.
This research defines a “potentially reversible neurodevelopmental path of risk that may be unique to schizophrenia,” the researchers write.
Although most individuals on this altered neurodevelopmental path likely “canalize” back toward normal development, some may not be rescued and instead “decanalize” toward illness, they add.
To date, prevention of schizophrenia from early life has seemed “unapproachable if not unimaginable, but these new insights offer possibilities to change the paradigm,” Dr. Weinberger said in the news release.
“Measuring schizophrenia genetic scores in the placenta combined with studying the first 2 years of cognitive developmental patterns and early life complications could prove to be an important approach to identify those babies with increased risks,” he added.
Important research
Commenting on the study for this news organization, Christopher A. Ross, MD, PhD, professor of psychiatry and behavioral sciences, Johns Hopkins Medicine, Baltimore, said that this is “an interesting and important paper that replicates and extends previous findings of the relationship of placenta genes to schizophrenia in adults.”
“The hypothesis continues to be – and they are continuing to support it – that events in early development could set a person up for a risk of schizophrenia later in life,” said Dr. Ross.
This research, he added, also supports the concept that there are at least two broad classes of genetic risk for schizophrenia.
“One acts through genes that are expressed in the brain and doesn’t relate to early life events, and the other acts through genes expressed in the placenta in patients with these early life events,” said Dr. Ross.
The study had no specific funding. Dr. Weinberger and Dr. Ross have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
With the exception of clozapine, the selection of an antipsychotic medication for acute treatment is driven by side effects.
Dr. Steven Marder
That’s a key pearl of wisdom that Stephen R. Marder, MD, shared during a discussion of key criteria for choosing an antipsychotic for patients with schizophrenia.
“It’s a decision that can have huge consequences, both to an individual’s mental health and their physical health,” Dr. Marder said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “If a patient did well and liked a prior antipsychotic, that’s usually evidence that they’ll respond again. That’s been shown numerous times. Aside from that, the largest consideration is usually adverse effects.”
In a multiple-treatments meta-analysis that compared the efficacy and tolerability of 15 antipsychotic drugs in schizophrenia, researchers found that an overall positive change in symptoms occurred with clozapine, compared with any other drug.
“Clozapine is not just the most effective antipsychotic for patients who are treatment resistant; it’s also the most effective antipsychotic in general populations,” said Dr. Marder, the Daniel X. Freedman Professor of Psychiatry at the Semel Institute for Neuroscience and Human Behavior at the University of California, Los Angeles. “The next most effective antipsychotic is amisulpride, which is not available in the U.S., although there’s a company that’s developing a formulation of amisulpride. After that, the 95% confidence intervals overlap, and the differences are probably related not to their true effectiveness but to other circumstances.”
For example, he continued, risperidone and olanzapine were developed in the 1990s. They were always compared with haloperidol and they tended to work a little bit better. “The drugs developed later on in clinical trials tended to be used in patients who were more treatment resistant,” he said. “Aside from clozapine, the differences in effectiveness are relatively small. But the differences in side effects are large.”
The meta-analysis found that haloperidol stood out as the antipsychotic most likely to cause extrapyramidal side effects. Olanzapine and clozapine stood out as causing the most weight gain, while ziprasidone and lurasidone were less likely to cause weight gain. In addition, risperidone, paliperidone, and haloperidol tended to cause the greatest elevation of prolactin levels, while aripiprazole was found to reduce prolactin levels.
“This becomes an important issue, particularly in young people when one is worried about galactorrhea in women or gynecomastia in men, which sometimes happens with risperidone or haloperidol, and to a lesser extent, sexual dysfunction,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education, and Clinical Center for the Department of Veterans Affairs. “Sedation is a major consideration for clozapine and chlorpromazine, but less for other antipsychotics.”
When do you know if you’ve selected the right medication for your patient? According to a meta-analysis of 42 studies involving 7,450 patients, improvement tends to occur within the first 2 weeks of treatment. “Which means if you put someone on an adequate dose of an antipsychotic and they haven’t improved in 2 weeks, there’s very little chance that they’re going to continue to improve,” Dr. Marder said. “This has been consequential because it provides guidance for clinicians to make decisions.”
Symptoms that are likely to improve in the first couple of days include agitation and psychomotor excitement. Improvement in psychotic symptoms typically occurs in the following order: those with thought disorder symptoms tend to develop more organized thinking, those with hallucinations tend to experience a decrease the intensity and frequency of their episodes, and those with well-ingrained delusions “tend to experience fewer misinterpretations,” Dr. Marder said. “They may feel less suspicious and they may talk less about delusions.”
Dr. Marder makes it a point to evaluate the antipsychotic response of patients in 2-3 weeks. “If it’s a partial response, continue a bit longer,” he advised. “It it’s no response, switch. And, of course, if the drug isn’t tolerated well, switch.”
He advised against thinking that patients can easily be categorized as being strong responders or nonresponders. Instead, he favors viewing responsiveness to an antipsychotic along a continuum. “Ten to fifteen percent of patients will fail to remit even at first exposure to an antipsychotic medication, but it’s more common that patients will be partial responders,” Dr. Marder said. “One will have to determine whether that response is adequate or not. There’s also the idea that patients sometimes respond vigorously to an antipsychotic early on. For example, first-episode patients tend to respond very well, and they respond at substantially lower doses. But I set a high criteria that we really want patients on an antipsychotic to respond well, to being in a remission that they can live with, not just to be partially remitted.”
In an analysis of response rates, 244 patients with first-episode schizophrenia moved through two antipsychotic trials, followed by a trial with clozapine. For the first two trials, treatment consisted of risperidone followed by olanzapine, or vice versa. About 75% of patients on either drug showed an initial response. “Among those who did not respond in the first trial but were switched to either drug, the response rate was very low, averaging about 16%,” Dr. Marder said. “In other words, if somebody responds poorly to risperidone, they’re not likely to respond to olanzapine, or vice versa. I think this is true among nearly all of the antipsychotic drugs that are available. Patients tend to have sort of an idiosyncratic ability to respond to a nonclozapine antipsychotic. They may respond to one better than the other, but oftentimes they won’t respond well.” When patients in the trial were switched to clozapine, 75% showed an adequate response.
Based on the study findings and on his own clinical practice, Dr. Marder recommends trying one or two antipsychotics before prescribing clozapine. “If they haven’t responded in a couple of weeks, it’s probably good to change them to another antipsychotic,” he said. “If the patient is responding poorly they should go on to clozapine, which I think is very underutilized.”
In late 2019, the Food and Drug Administration approved lumateperone, a presynaptic D2 partial agonist and a postsynaptic D2 antagonist, for the treatment of schizophrenia in adults. “Its dopamine blockage doesn’t lead to increased dopamine, so it seems to work differently than other antipsychotics,” Dr. Marder said. “It’s effective at lower D2 affinity, which is similar to drugs like clozapine, and it has greater 5 HT2A:D2 antagonism.” It appears to have a relatively benign safety profile, including minimal weight gain, minimal metabolic adverse effects, and minimal extrapyramidal effects. “However, I think the jury’s out,” he added. “There is very little information about head-to-head comparisons between lumateperone and other antipsychotics.”
The new kid on the block is the Alkermes agent AKLS 3831, a combination drug of olanzapine-samidorphan, for the treatment of adults with schizophrenia and adults with bipolar I disorder. In December 2020, the FDA accepted the company’s New Drug Application and set the Prescription Drug User Fee Act target action date of June 1, 2021. Results from a phase 2 trial demonstrated mitigation of olanzapine-induced weight gain with the opioid antagonist samidorphan. “This is not a weight-loss drug,” Dr. Marder said. “It’s just a formulation that causes less weight gain. For patients who do well on olanzapine, putting them on this combination may be helpful in preventing weight gain.”
Dr. Marder disclosed that he has served as a consultant for AbbVie, Allergan, Boehringer Ingelheim, Forum, Genentech, Lundbeck, Neurocrine, Otsuka, Roche, Sunovion, Takeda, Targacept, and Teva. He has also received research support from Boehringer Ingelheim, Neurocrine, and Takeda, and is a section editor for UpToDate.
With the exception of clozapine, the selection of an antipsychotic medication for acute treatment is driven by side effects.
Dr. Steven Marder
That’s a key pearl of wisdom that Stephen R. Marder, MD, shared during a discussion of key criteria for choosing an antipsychotic for patients with schizophrenia.
“It’s a decision that can have huge consequences, both to an individual’s mental health and their physical health,” Dr. Marder said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “If a patient did well and liked a prior antipsychotic, that’s usually evidence that they’ll respond again. That’s been shown numerous times. Aside from that, the largest consideration is usually adverse effects.”
In a multiple-treatments meta-analysis that compared the efficacy and tolerability of 15 antipsychotic drugs in schizophrenia, researchers found that an overall positive change in symptoms occurred with clozapine, compared with any other drug.
“Clozapine is not just the most effective antipsychotic for patients who are treatment resistant; it’s also the most effective antipsychotic in general populations,” said Dr. Marder, the Daniel X. Freedman Professor of Psychiatry at the Semel Institute for Neuroscience and Human Behavior at the University of California, Los Angeles. “The next most effective antipsychotic is amisulpride, which is not available in the U.S., although there’s a company that’s developing a formulation of amisulpride. After that, the 95% confidence intervals overlap, and the differences are probably related not to their true effectiveness but to other circumstances.”
For example, he continued, risperidone and olanzapine were developed in the 1990s. They were always compared with haloperidol and they tended to work a little bit better. “The drugs developed later on in clinical trials tended to be used in patients who were more treatment resistant,” he said. “Aside from clozapine, the differences in effectiveness are relatively small. But the differences in side effects are large.”
The meta-analysis found that haloperidol stood out as the antipsychotic most likely to cause extrapyramidal side effects. Olanzapine and clozapine stood out as causing the most weight gain, while ziprasidone and lurasidone were less likely to cause weight gain. In addition, risperidone, paliperidone, and haloperidol tended to cause the greatest elevation of prolactin levels, while aripiprazole was found to reduce prolactin levels.
“This becomes an important issue, particularly in young people when one is worried about galactorrhea in women or gynecomastia in men, which sometimes happens with risperidone or haloperidol, and to a lesser extent, sexual dysfunction,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education, and Clinical Center for the Department of Veterans Affairs. “Sedation is a major consideration for clozapine and chlorpromazine, but less for other antipsychotics.”
When do you know if you’ve selected the right medication for your patient? According to a meta-analysis of 42 studies involving 7,450 patients, improvement tends to occur within the first 2 weeks of treatment. “Which means if you put someone on an adequate dose of an antipsychotic and they haven’t improved in 2 weeks, there’s very little chance that they’re going to continue to improve,” Dr. Marder said. “This has been consequential because it provides guidance for clinicians to make decisions.”
Symptoms that are likely to improve in the first couple of days include agitation and psychomotor excitement. Improvement in psychotic symptoms typically occurs in the following order: those with thought disorder symptoms tend to develop more organized thinking, those with hallucinations tend to experience a decrease the intensity and frequency of their episodes, and those with well-ingrained delusions “tend to experience fewer misinterpretations,” Dr. Marder said. “They may feel less suspicious and they may talk less about delusions.”
Dr. Marder makes it a point to evaluate the antipsychotic response of patients in 2-3 weeks. “If it’s a partial response, continue a bit longer,” he advised. “It it’s no response, switch. And, of course, if the drug isn’t tolerated well, switch.”
He advised against thinking that patients can easily be categorized as being strong responders or nonresponders. Instead, he favors viewing responsiveness to an antipsychotic along a continuum. “Ten to fifteen percent of patients will fail to remit even at first exposure to an antipsychotic medication, but it’s more common that patients will be partial responders,” Dr. Marder said. “One will have to determine whether that response is adequate or not. There’s also the idea that patients sometimes respond vigorously to an antipsychotic early on. For example, first-episode patients tend to respond very well, and they respond at substantially lower doses. But I set a high criteria that we really want patients on an antipsychotic to respond well, to being in a remission that they can live with, not just to be partially remitted.”
In an analysis of response rates, 244 patients with first-episode schizophrenia moved through two antipsychotic trials, followed by a trial with clozapine. For the first two trials, treatment consisted of risperidone followed by olanzapine, or vice versa. About 75% of patients on either drug showed an initial response. “Among those who did not respond in the first trial but were switched to either drug, the response rate was very low, averaging about 16%,” Dr. Marder said. “In other words, if somebody responds poorly to risperidone, they’re not likely to respond to olanzapine, or vice versa. I think this is true among nearly all of the antipsychotic drugs that are available. Patients tend to have sort of an idiosyncratic ability to respond to a nonclozapine antipsychotic. They may respond to one better than the other, but oftentimes they won’t respond well.” When patients in the trial were switched to clozapine, 75% showed an adequate response.
Based on the study findings and on his own clinical practice, Dr. Marder recommends trying one or two antipsychotics before prescribing clozapine. “If they haven’t responded in a couple of weeks, it’s probably good to change them to another antipsychotic,” he said. “If the patient is responding poorly they should go on to clozapine, which I think is very underutilized.”
In late 2019, the Food and Drug Administration approved lumateperone, a presynaptic D2 partial agonist and a postsynaptic D2 antagonist, for the treatment of schizophrenia in adults. “Its dopamine blockage doesn’t lead to increased dopamine, so it seems to work differently than other antipsychotics,” Dr. Marder said. “It’s effective at lower D2 affinity, which is similar to drugs like clozapine, and it has greater 5 HT2A:D2 antagonism.” It appears to have a relatively benign safety profile, including minimal weight gain, minimal metabolic adverse effects, and minimal extrapyramidal effects. “However, I think the jury’s out,” he added. “There is very little information about head-to-head comparisons between lumateperone and other antipsychotics.”
The new kid on the block is the Alkermes agent AKLS 3831, a combination drug of olanzapine-samidorphan, for the treatment of adults with schizophrenia and adults with bipolar I disorder. In December 2020, the FDA accepted the company’s New Drug Application and set the Prescription Drug User Fee Act target action date of June 1, 2021. Results from a phase 2 trial demonstrated mitigation of olanzapine-induced weight gain with the opioid antagonist samidorphan. “This is not a weight-loss drug,” Dr. Marder said. “It’s just a formulation that causes less weight gain. For patients who do well on olanzapine, putting them on this combination may be helpful in preventing weight gain.”
Dr. Marder disclosed that he has served as a consultant for AbbVie, Allergan, Boehringer Ingelheim, Forum, Genentech, Lundbeck, Neurocrine, Otsuka, Roche, Sunovion, Takeda, Targacept, and Teva. He has also received research support from Boehringer Ingelheim, Neurocrine, and Takeda, and is a section editor for UpToDate.
With the exception of clozapine, the selection of an antipsychotic medication for acute treatment is driven by side effects.
Dr. Steven Marder
That’s a key pearl of wisdom that Stephen R. Marder, MD, shared during a discussion of key criteria for choosing an antipsychotic for patients with schizophrenia.
“It’s a decision that can have huge consequences, both to an individual’s mental health and their physical health,” Dr. Marder said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “If a patient did well and liked a prior antipsychotic, that’s usually evidence that they’ll respond again. That’s been shown numerous times. Aside from that, the largest consideration is usually adverse effects.”
In a multiple-treatments meta-analysis that compared the efficacy and tolerability of 15 antipsychotic drugs in schizophrenia, researchers found that an overall positive change in symptoms occurred with clozapine, compared with any other drug.
“Clozapine is not just the most effective antipsychotic for patients who are treatment resistant; it’s also the most effective antipsychotic in general populations,” said Dr. Marder, the Daniel X. Freedman Professor of Psychiatry at the Semel Institute for Neuroscience and Human Behavior at the University of California, Los Angeles. “The next most effective antipsychotic is amisulpride, which is not available in the U.S., although there’s a company that’s developing a formulation of amisulpride. After that, the 95% confidence intervals overlap, and the differences are probably related not to their true effectiveness but to other circumstances.”
For example, he continued, risperidone and olanzapine were developed in the 1990s. They were always compared with haloperidol and they tended to work a little bit better. “The drugs developed later on in clinical trials tended to be used in patients who were more treatment resistant,” he said. “Aside from clozapine, the differences in effectiveness are relatively small. But the differences in side effects are large.”
The meta-analysis found that haloperidol stood out as the antipsychotic most likely to cause extrapyramidal side effects. Olanzapine and clozapine stood out as causing the most weight gain, while ziprasidone and lurasidone were less likely to cause weight gain. In addition, risperidone, paliperidone, and haloperidol tended to cause the greatest elevation of prolactin levels, while aripiprazole was found to reduce prolactin levels.
“This becomes an important issue, particularly in young people when one is worried about galactorrhea in women or gynecomastia in men, which sometimes happens with risperidone or haloperidol, and to a lesser extent, sexual dysfunction,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education, and Clinical Center for the Department of Veterans Affairs. “Sedation is a major consideration for clozapine and chlorpromazine, but less for other antipsychotics.”
When do you know if you’ve selected the right medication for your patient? According to a meta-analysis of 42 studies involving 7,450 patients, improvement tends to occur within the first 2 weeks of treatment. “Which means if you put someone on an adequate dose of an antipsychotic and they haven’t improved in 2 weeks, there’s very little chance that they’re going to continue to improve,” Dr. Marder said. “This has been consequential because it provides guidance for clinicians to make decisions.”
Symptoms that are likely to improve in the first couple of days include agitation and psychomotor excitement. Improvement in psychotic symptoms typically occurs in the following order: those with thought disorder symptoms tend to develop more organized thinking, those with hallucinations tend to experience a decrease the intensity and frequency of their episodes, and those with well-ingrained delusions “tend to experience fewer misinterpretations,” Dr. Marder said. “They may feel less suspicious and they may talk less about delusions.”
Dr. Marder makes it a point to evaluate the antipsychotic response of patients in 2-3 weeks. “If it’s a partial response, continue a bit longer,” he advised. “It it’s no response, switch. And, of course, if the drug isn’t tolerated well, switch.”
He advised against thinking that patients can easily be categorized as being strong responders or nonresponders. Instead, he favors viewing responsiveness to an antipsychotic along a continuum. “Ten to fifteen percent of patients will fail to remit even at first exposure to an antipsychotic medication, but it’s more common that patients will be partial responders,” Dr. Marder said. “One will have to determine whether that response is adequate or not. There’s also the idea that patients sometimes respond vigorously to an antipsychotic early on. For example, first-episode patients tend to respond very well, and they respond at substantially lower doses. But I set a high criteria that we really want patients on an antipsychotic to respond well, to being in a remission that they can live with, not just to be partially remitted.”
In an analysis of response rates, 244 patients with first-episode schizophrenia moved through two antipsychotic trials, followed by a trial with clozapine. For the first two trials, treatment consisted of risperidone followed by olanzapine, or vice versa. About 75% of patients on either drug showed an initial response. “Among those who did not respond in the first trial but were switched to either drug, the response rate was very low, averaging about 16%,” Dr. Marder said. “In other words, if somebody responds poorly to risperidone, they’re not likely to respond to olanzapine, or vice versa. I think this is true among nearly all of the antipsychotic drugs that are available. Patients tend to have sort of an idiosyncratic ability to respond to a nonclozapine antipsychotic. They may respond to one better than the other, but oftentimes they won’t respond well.” When patients in the trial were switched to clozapine, 75% showed an adequate response.
Based on the study findings and on his own clinical practice, Dr. Marder recommends trying one or two antipsychotics before prescribing clozapine. “If they haven’t responded in a couple of weeks, it’s probably good to change them to another antipsychotic,” he said. “If the patient is responding poorly they should go on to clozapine, which I think is very underutilized.”
In late 2019, the Food and Drug Administration approved lumateperone, a presynaptic D2 partial agonist and a postsynaptic D2 antagonist, for the treatment of schizophrenia in adults. “Its dopamine blockage doesn’t lead to increased dopamine, so it seems to work differently than other antipsychotics,” Dr. Marder said. “It’s effective at lower D2 affinity, which is similar to drugs like clozapine, and it has greater 5 HT2A:D2 antagonism.” It appears to have a relatively benign safety profile, including minimal weight gain, minimal metabolic adverse effects, and minimal extrapyramidal effects. “However, I think the jury’s out,” he added. “There is very little information about head-to-head comparisons between lumateperone and other antipsychotics.”
The new kid on the block is the Alkermes agent AKLS 3831, a combination drug of olanzapine-samidorphan, for the treatment of adults with schizophrenia and adults with bipolar I disorder. In December 2020, the FDA accepted the company’s New Drug Application and set the Prescription Drug User Fee Act target action date of June 1, 2021. Results from a phase 2 trial demonstrated mitigation of olanzapine-induced weight gain with the opioid antagonist samidorphan. “This is not a weight-loss drug,” Dr. Marder said. “It’s just a formulation that causes less weight gain. For patients who do well on olanzapine, putting them on this combination may be helpful in preventing weight gain.”
Dr. Marder disclosed that he has served as a consultant for AbbVie, Allergan, Boehringer Ingelheim, Forum, Genentech, Lundbeck, Neurocrine, Otsuka, Roche, Sunovion, Takeda, Targacept, and Teva. He has also received research support from Boehringer Ingelheim, Neurocrine, and Takeda, and is a section editor for UpToDate.
Now that completion of residency is fast approaching, I am asked regularly what I plan to do when I become a Real Doctor on July 1. It feels like it wasn’t so long ago I was trying to decide if I should even go to medical school, then later, if I should go into psychiatry, family medicine, or emergency medicine. And here I am at another decision point, another of the regular, 4-year milestones in my journey to full physicianhood.
Dr. Ashley Stone
A surprising thing happened to me during my psychiatry training: I fell in love with acute care. Instead of outpatient care, I preferred the longer hours with patients who insist they are Jesus Christ, believe deeply they are being actively pursued by the FBI, and sometimes eat their own feces. I was in awe of the remarkable capacity of the human brain to convince a graduate-school educated man with bipolar disorder that it is acceptable to call in bomb threats to a hospital. To lead a patient on a conservatorship to believe that I am not a doctor but, instead, a seamstress or leave socks full of feces as presents for Santa Claus (lots of feces in inpatient psychiatry). To believe their spouses are not humans or hear voices telling them they should jump off a bridge, sustaining near-lethal injuries. I was hooked.
Psychiatry as a field is not for those requiring instant gratification. Other than Ativan challenges and the remarkably quick response some patients have to ECT, outcomes of our treatments are usually modest, and they take time. We often delude ourselves into thinking that bumping a patient’s fluoxetine from 10 mg to 20 mg will be The Thing that changes a patient’s life. We address our own sense of helplessness as much as that of our patients, who are desperate for something, for someone, to do something that will alter the course of their lives.
Of course, what I can offer my patients usually falls short of their lofty expectations of my prowess. I offer them compassion, validation, empathy. I offer them medications for which we usually have meager data and meager results. I cannot find them shelter but for a few nights, perhaps a week. I rarely, in settings in which primary diagnoses of substance use and personality disorders are forbidden by insurance companies, can help them with their addiction to methamphetamine. I cannot cure their maladaptive characterological pathology stemming from childhood attachment trauma. To address my own sense of failure as a healer, I resort to the bottom of Maslow’s hierarchy of needs, providing their choice of juice box, more blankets. I slow-roll their discharges overnight so that they can stay in the ER hallway instead of spending the night outside in the rare Southern California rain.
In my 3rd year of residency, we were thrown into a pandemic. I felt both terrified of getting COVID-19 in the hospital and inadequate as a physician. I did not want to be intubating patients, but even more, I dreaded the potential “psychiatry-friendly” assignment of calling the family members of those who had perished from the disease. Rumors circulated that certain versions of surge planning had the inpatient psychiatry unit transitioned to a COVID unit and psychiatry residents “redeployed” to cover medicine floors. Fortunately, we did not have to (or have not yet had to) endure this apocalyptic episode of worst-case scenario. I remained a psychiatrist-in-training, seeing occasional COVID patients but with full personal protective equipment and the ability to maintain some physical distance to complete my examinations. Coming home to my apartment building in scrubs, now acceptable attire on inpatient units – it always should have been since, as we have established, our units are filled with feces – I early on felt like a leper. Later on, I was treated with dignity and respect, like a hero.
My position as a non–frontline-physician was personally challenging. I wanted to help, felt like I should and could help. I am a helper-in-recovery who has spent years learning to achieve a balance of service and loyalty to others and my own desires. The initial guilt I felt at feeling appreciated during the nightly celebration of health care workers downtown ultimately dissipated. I was no hero, nor did I claim to be one. I made peace with my pandemic hobbies of sourdough bread-baking, Moscow mule-making, jigsaw-puzzling, and, briefly, running (before a calcaneal stress fracture reminded me that I am not built for land exercise). I went to work; I came home. My cat was happy.
Then, in rapid succession, vaccines were approved and distributed. My hospital had partnered with the county to administer them at a new superstation, and they were in desperate need of licensed humans to be vaccinators. They cared not that I had given very few (n = 3) injections and only during medical school. I watched the YouTube videos on the Z-track technique for IMs, learned about needle gauges, and went off to the baseball stadium.
I loved this new gig, disproportionately. The 8+ hours flew by, 100 vaccines given to occupants of cars who had eagerly waited hours for the privilege of being vaccinated by an almost-psychiatrist. It was not the technical expertise of sticking a needle into someone’s arm that gave me a dopamine rush, nor the microstress of preparing the syringes with a flimsy needle and a slight caffeine-induced tremor while trying to flick air bubbles out of the syringe without dropping the precious vaccine vial. It was not the travel nurse asking me why anyone – especially an overworked resident – would volunteer to do this for free, while she and others were making “stupid amounts of money” to do the same job.
What drove me to keep volunteering for no pay, only Cheez-Its available as sustenance, minimal gratitude from my employer, long hours on my feet doing a task that was rote and at which I probably would never completely excel? On my second shift, I realized why I found it so gratifying to be a vaccinator: There was a perfect 1:1 correspondence in what patients wanted at that moment and in what I had to offer them. They did not want me to fix their lives, secure them housing, or go back in time and remove them from abusive homes so they could grow up to be more functional, happier adults. They merely wanted a shot. They were profusely grateful, hopeful that this was the Beginning of the End. Nobody spat on me; nobody called me obscene names. Nobody was upset with me for involuntarily holding them against their will. My services were welcome, appreciated. I had lovely, superficial conversations with dozens of people. I felt connected to strangers in a way that has been sorely lacking since March 2020. Understandably mistaken for a nurse throughout the day, I felt more like a bona fide physician than I had in over a year.
I know the adrenaline rush will fade, that volunteer-vaccinating in my free time will eventually become less exciting to me. I know I won’t be able to convince my colleagues indefinitely that volunteering together is a great, institution-sanctioned bonding opportunity. I know the initial enthusiasm over vaccine distribution will fade as the pandemic continues to transform our everyday lives and threaten the health of millions, the economy, and the sanctity of normal human interactions. The gratitude and hopefulness may well be replaced with frustration over waiting hours in a car to get an injection from a psychiatrist, with fear that this promised panacea may not restore normalcy anytime soon. But right now, 11 months into a pandemic that has left our profession exhausted and jaded, the coprophilia and catatonia have temporarily lost their allure. So, I’m adding “vaccinator” to my list of pandemic hobbies.
Dr. Stone is a chief resident in psychiatry at the University of California, San Diego. Before deciding to become a physician, she obtained a master’s degree in public health and worked in health policy research studying empathy and patient-doctor interactions. She has a passion for public psychiatry and acute care, and she dabbles in physician wellness, medical education, and the interface of psychiatry and primary care. Dr. Stone has no disclosures.
Now that completion of residency is fast approaching, I am asked regularly what I plan to do when I become a Real Doctor on July 1. It feels like it wasn’t so long ago I was trying to decide if I should even go to medical school, then later, if I should go into psychiatry, family medicine, or emergency medicine. And here I am at another decision point, another of the regular, 4-year milestones in my journey to full physicianhood.
Dr. Ashley Stone
A surprising thing happened to me during my psychiatry training: I fell in love with acute care. Instead of outpatient care, I preferred the longer hours with patients who insist they are Jesus Christ, believe deeply they are being actively pursued by the FBI, and sometimes eat their own feces. I was in awe of the remarkable capacity of the human brain to convince a graduate-school educated man with bipolar disorder that it is acceptable to call in bomb threats to a hospital. To lead a patient on a conservatorship to believe that I am not a doctor but, instead, a seamstress or leave socks full of feces as presents for Santa Claus (lots of feces in inpatient psychiatry). To believe their spouses are not humans or hear voices telling them they should jump off a bridge, sustaining near-lethal injuries. I was hooked.
Psychiatry as a field is not for those requiring instant gratification. Other than Ativan challenges and the remarkably quick response some patients have to ECT, outcomes of our treatments are usually modest, and they take time. We often delude ourselves into thinking that bumping a patient’s fluoxetine from 10 mg to 20 mg will be The Thing that changes a patient’s life. We address our own sense of helplessness as much as that of our patients, who are desperate for something, for someone, to do something that will alter the course of their lives.
Of course, what I can offer my patients usually falls short of their lofty expectations of my prowess. I offer them compassion, validation, empathy. I offer them medications for which we usually have meager data and meager results. I cannot find them shelter but for a few nights, perhaps a week. I rarely, in settings in which primary diagnoses of substance use and personality disorders are forbidden by insurance companies, can help them with their addiction to methamphetamine. I cannot cure their maladaptive characterological pathology stemming from childhood attachment trauma. To address my own sense of failure as a healer, I resort to the bottom of Maslow’s hierarchy of needs, providing their choice of juice box, more blankets. I slow-roll their discharges overnight so that they can stay in the ER hallway instead of spending the night outside in the rare Southern California rain.
In my 3rd year of residency, we were thrown into a pandemic. I felt both terrified of getting COVID-19 in the hospital and inadequate as a physician. I did not want to be intubating patients, but even more, I dreaded the potential “psychiatry-friendly” assignment of calling the family members of those who had perished from the disease. Rumors circulated that certain versions of surge planning had the inpatient psychiatry unit transitioned to a COVID unit and psychiatry residents “redeployed” to cover medicine floors. Fortunately, we did not have to (or have not yet had to) endure this apocalyptic episode of worst-case scenario. I remained a psychiatrist-in-training, seeing occasional COVID patients but with full personal protective equipment and the ability to maintain some physical distance to complete my examinations. Coming home to my apartment building in scrubs, now acceptable attire on inpatient units – it always should have been since, as we have established, our units are filled with feces – I early on felt like a leper. Later on, I was treated with dignity and respect, like a hero.
My position as a non–frontline-physician was personally challenging. I wanted to help, felt like I should and could help. I am a helper-in-recovery who has spent years learning to achieve a balance of service and loyalty to others and my own desires. The initial guilt I felt at feeling appreciated during the nightly celebration of health care workers downtown ultimately dissipated. I was no hero, nor did I claim to be one. I made peace with my pandemic hobbies of sourdough bread-baking, Moscow mule-making, jigsaw-puzzling, and, briefly, running (before a calcaneal stress fracture reminded me that I am not built for land exercise). I went to work; I came home. My cat was happy.
Then, in rapid succession, vaccines were approved and distributed. My hospital had partnered with the county to administer them at a new superstation, and they were in desperate need of licensed humans to be vaccinators. They cared not that I had given very few (n = 3) injections and only during medical school. I watched the YouTube videos on the Z-track technique for IMs, learned about needle gauges, and went off to the baseball stadium.
I loved this new gig, disproportionately. The 8+ hours flew by, 100 vaccines given to occupants of cars who had eagerly waited hours for the privilege of being vaccinated by an almost-psychiatrist. It was not the technical expertise of sticking a needle into someone’s arm that gave me a dopamine rush, nor the microstress of preparing the syringes with a flimsy needle and a slight caffeine-induced tremor while trying to flick air bubbles out of the syringe without dropping the precious vaccine vial. It was not the travel nurse asking me why anyone – especially an overworked resident – would volunteer to do this for free, while she and others were making “stupid amounts of money” to do the same job.
What drove me to keep volunteering for no pay, only Cheez-Its available as sustenance, minimal gratitude from my employer, long hours on my feet doing a task that was rote and at which I probably would never completely excel? On my second shift, I realized why I found it so gratifying to be a vaccinator: There was a perfect 1:1 correspondence in what patients wanted at that moment and in what I had to offer them. They did not want me to fix their lives, secure them housing, or go back in time and remove them from abusive homes so they could grow up to be more functional, happier adults. They merely wanted a shot. They were profusely grateful, hopeful that this was the Beginning of the End. Nobody spat on me; nobody called me obscene names. Nobody was upset with me for involuntarily holding them against their will. My services were welcome, appreciated. I had lovely, superficial conversations with dozens of people. I felt connected to strangers in a way that has been sorely lacking since March 2020. Understandably mistaken for a nurse throughout the day, I felt more like a bona fide physician than I had in over a year.
I know the adrenaline rush will fade, that volunteer-vaccinating in my free time will eventually become less exciting to me. I know I won’t be able to convince my colleagues indefinitely that volunteering together is a great, institution-sanctioned bonding opportunity. I know the initial enthusiasm over vaccine distribution will fade as the pandemic continues to transform our everyday lives and threaten the health of millions, the economy, and the sanctity of normal human interactions. The gratitude and hopefulness may well be replaced with frustration over waiting hours in a car to get an injection from a psychiatrist, with fear that this promised panacea may not restore normalcy anytime soon. But right now, 11 months into a pandemic that has left our profession exhausted and jaded, the coprophilia and catatonia have temporarily lost their allure. So, I’m adding “vaccinator” to my list of pandemic hobbies.
Dr. Stone is a chief resident in psychiatry at the University of California, San Diego. Before deciding to become a physician, she obtained a master’s degree in public health and worked in health policy research studying empathy and patient-doctor interactions. She has a passion for public psychiatry and acute care, and she dabbles in physician wellness, medical education, and the interface of psychiatry and primary care. Dr. Stone has no disclosures.
Now that completion of residency is fast approaching, I am asked regularly what I plan to do when I become a Real Doctor on July 1. It feels like it wasn’t so long ago I was trying to decide if I should even go to medical school, then later, if I should go into psychiatry, family medicine, or emergency medicine. And here I am at another decision point, another of the regular, 4-year milestones in my journey to full physicianhood.
Dr. Ashley Stone
A surprising thing happened to me during my psychiatry training: I fell in love with acute care. Instead of outpatient care, I preferred the longer hours with patients who insist they are Jesus Christ, believe deeply they are being actively pursued by the FBI, and sometimes eat their own feces. I was in awe of the remarkable capacity of the human brain to convince a graduate-school educated man with bipolar disorder that it is acceptable to call in bomb threats to a hospital. To lead a patient on a conservatorship to believe that I am not a doctor but, instead, a seamstress or leave socks full of feces as presents for Santa Claus (lots of feces in inpatient psychiatry). To believe their spouses are not humans or hear voices telling them they should jump off a bridge, sustaining near-lethal injuries. I was hooked.
Psychiatry as a field is not for those requiring instant gratification. Other than Ativan challenges and the remarkably quick response some patients have to ECT, outcomes of our treatments are usually modest, and they take time. We often delude ourselves into thinking that bumping a patient’s fluoxetine from 10 mg to 20 mg will be The Thing that changes a patient’s life. We address our own sense of helplessness as much as that of our patients, who are desperate for something, for someone, to do something that will alter the course of their lives.
Of course, what I can offer my patients usually falls short of their lofty expectations of my prowess. I offer them compassion, validation, empathy. I offer them medications for which we usually have meager data and meager results. I cannot find them shelter but for a few nights, perhaps a week. I rarely, in settings in which primary diagnoses of substance use and personality disorders are forbidden by insurance companies, can help them with their addiction to methamphetamine. I cannot cure their maladaptive characterological pathology stemming from childhood attachment trauma. To address my own sense of failure as a healer, I resort to the bottom of Maslow’s hierarchy of needs, providing their choice of juice box, more blankets. I slow-roll their discharges overnight so that they can stay in the ER hallway instead of spending the night outside in the rare Southern California rain.
In my 3rd year of residency, we were thrown into a pandemic. I felt both terrified of getting COVID-19 in the hospital and inadequate as a physician. I did not want to be intubating patients, but even more, I dreaded the potential “psychiatry-friendly” assignment of calling the family members of those who had perished from the disease. Rumors circulated that certain versions of surge planning had the inpatient psychiatry unit transitioned to a COVID unit and psychiatry residents “redeployed” to cover medicine floors. Fortunately, we did not have to (or have not yet had to) endure this apocalyptic episode of worst-case scenario. I remained a psychiatrist-in-training, seeing occasional COVID patients but with full personal protective equipment and the ability to maintain some physical distance to complete my examinations. Coming home to my apartment building in scrubs, now acceptable attire on inpatient units – it always should have been since, as we have established, our units are filled with feces – I early on felt like a leper. Later on, I was treated with dignity and respect, like a hero.
My position as a non–frontline-physician was personally challenging. I wanted to help, felt like I should and could help. I am a helper-in-recovery who has spent years learning to achieve a balance of service and loyalty to others and my own desires. The initial guilt I felt at feeling appreciated during the nightly celebration of health care workers downtown ultimately dissipated. I was no hero, nor did I claim to be one. I made peace with my pandemic hobbies of sourdough bread-baking, Moscow mule-making, jigsaw-puzzling, and, briefly, running (before a calcaneal stress fracture reminded me that I am not built for land exercise). I went to work; I came home. My cat was happy.
Then, in rapid succession, vaccines were approved and distributed. My hospital had partnered with the county to administer them at a new superstation, and they were in desperate need of licensed humans to be vaccinators. They cared not that I had given very few (n = 3) injections and only during medical school. I watched the YouTube videos on the Z-track technique for IMs, learned about needle gauges, and went off to the baseball stadium.
I loved this new gig, disproportionately. The 8+ hours flew by, 100 vaccines given to occupants of cars who had eagerly waited hours for the privilege of being vaccinated by an almost-psychiatrist. It was not the technical expertise of sticking a needle into someone’s arm that gave me a dopamine rush, nor the microstress of preparing the syringes with a flimsy needle and a slight caffeine-induced tremor while trying to flick air bubbles out of the syringe without dropping the precious vaccine vial. It was not the travel nurse asking me why anyone – especially an overworked resident – would volunteer to do this for free, while she and others were making “stupid amounts of money” to do the same job.
What drove me to keep volunteering for no pay, only Cheez-Its available as sustenance, minimal gratitude from my employer, long hours on my feet doing a task that was rote and at which I probably would never completely excel? On my second shift, I realized why I found it so gratifying to be a vaccinator: There was a perfect 1:1 correspondence in what patients wanted at that moment and in what I had to offer them. They did not want me to fix their lives, secure them housing, or go back in time and remove them from abusive homes so they could grow up to be more functional, happier adults. They merely wanted a shot. They were profusely grateful, hopeful that this was the Beginning of the End. Nobody spat on me; nobody called me obscene names. Nobody was upset with me for involuntarily holding them against their will. My services were welcome, appreciated. I had lovely, superficial conversations with dozens of people. I felt connected to strangers in a way that has been sorely lacking since March 2020. Understandably mistaken for a nurse throughout the day, I felt more like a bona fide physician than I had in over a year.
I know the adrenaline rush will fade, that volunteer-vaccinating in my free time will eventually become less exciting to me. I know I won’t be able to convince my colleagues indefinitely that volunteering together is a great, institution-sanctioned bonding opportunity. I know the initial enthusiasm over vaccine distribution will fade as the pandemic continues to transform our everyday lives and threaten the health of millions, the economy, and the sanctity of normal human interactions. The gratitude and hopefulness may well be replaced with frustration over waiting hours in a car to get an injection from a psychiatrist, with fear that this promised panacea may not restore normalcy anytime soon. But right now, 11 months into a pandemic that has left our profession exhausted and jaded, the coprophilia and catatonia have temporarily lost their allure. So, I’m adding “vaccinator” to my list of pandemic hobbies.
Dr. Stone is a chief resident in psychiatry at the University of California, San Diego. Before deciding to become a physician, she obtained a master’s degree in public health and worked in health policy research studying empathy and patient-doctor interactions. She has a passion for public psychiatry and acute care, and she dabbles in physician wellness, medical education, and the interface of psychiatry and primary care. Dr. Stone has no disclosures.
Psychiatrists with expertise in delusional infestation have some advice for dermatologists, infectious disease specialists, and primary care physicians who encounter affected patients: If you want to try to help them, initiate treatment yourself.
Dr. Peter Lepping
“If you see it, try and treat it. These patients are unlikely to agree to see a psychiatrist,” Peter Lepping, MD, said at the Entomology 2020 annual meeting.
Indeed, one of the hallmarks of delusional infestation (DI) is a refusal to even consider referral to a mental health professional, noted Dr. Lepping, a consultation-liaison psychiatrist at Bangor (Wales) University who, together with an infectious disease specialist, codirects one of the world’s few DI multispecialty referral clinics, located at the University of Liverpool School of Tropical Medicine.
That being said, he offered another piece of advice: “Accept that it is not easy to help these patients.”
Dr. Lepping was among a group of distinguished psychiatrists, dermatologists, entomologists, and a neurologist at the annual meeting who participated in a comprehensive session devoted to DI. The experts shared tips on making the diagnosis, establishing the rapport necessary to persuade affected patients to try taking a very-low-dose antipsychotic agent for their delusion, and how to achieve a high rate of therapeutic success. They also highlighted recent research advances in the field, including brain MRI evidence suggesting that impaired somatosensory neural networks mediate symptoms in DI, but not in nonsomatic delusional disorders.
COVID-19 pandemic triggers surge in DI
Entomologist Gail E. Ridge, PhD, has taken notes on all of her thousands of consultations with individuals with suspected DI since the late 1990s. A sharp jump in such contacts occurred during the Great Recession of 2008 in conjunction with the widespread social distress of job loss and threatened economic ruin. Now the same thing is happening as the catastrophic COVID-19 pandemic stretches on. Indeed, during the first 8 months of the pandemic she documented 500 interactions involving people with suspected DI. She’s learned to identify the clues, including a chattering mind, defensiveness, physician avoidance, and rigid body tension.
Courtesy Dr. Gale E. Ridge
Dr. Gale E. Ridge
“They’re fearful of judgment and suggestions of madness. And they’ll pounce on any perceived negativity. I never debunk beliefs; that can immediately backfire. If the medical profession was educated about DI, then many cases could be caught early. I, as the entomologist, and the mental health professionals are often last in line to be seen,” said Dr. Ridge, director of the Insect Information Office at the Connecticut Agricultural Experiment Station in New Haven.
She has noticed a recurring theme in her interactions with these patients: DI often starts with a real underlying medical condition, such as, for example, a cutaneous drug reaction, which over time, progresses to gain a psychiatric component. And she has found that a tipping point often occurs after roughly 6 months of unrelieved symptoms and sensations. Prior to that, affected individuals are concerned about their condition and will seek medical help in a genuine effort to understand what’s going on. They can be redirected. After about 6 months, however, Dr. Ridge has observed “they slide into the rabbit hole of fanaticism and despair.”
Arriving at the diagnosis
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), DI is classified as a “delusional disorder, somatic type 297.1 F22.” The diagnosis requires that the delusion be present for at least 1 month, criteria for schizophrenia are not met, and the condition cannot be attributed to other medical or neuropsychiatric conditions.
“Many of these people are very high-functioning. I have corporate CEOs who fly in to see me in their private jets. At work, they’re king of their domain. At home, their family is falling apart because of their delusion,” said Dirk M. Elston, MD, professor and chair of the department of dermatology and dermatologic surgery at the Medical University of South Carolina, Charleston.
Dr. Dirk M. Elston
“These people suffer, and the people around them suffer,” he emphasized.
Dozens of medical conditions can cause intractable itching or biting sensations. Far and away at the top of the medical differential diagnosis is thyroid disease, given its high incidence and frequent presentation with anxiety and itch. Other possibilities that can readily be ruled out via lab tests include substance use – especially involving amphetamine/methamphetamine, cocaine, or opioids – liver or kidney disease, diabetes and other sources of peripheral neuropathy, polycythemia, dermatitis herpetiformis, and pemphigus, Dr. Elston said.
Scott A. Norton, MD, MPH, MSc, a dermatologist and preventive medicine specialist at the Uniformed Services University of the Health Sciences in Bethesda, Md., noted that a diagnosis of DI requires three elements: The presence of abnormal sensations in the skin, a patient’s tenacious conviction that the sensations are caused by an infestation, and a lack of supporting evidence for that conviction.
Dr. Scott A. Norton
Taking an accurate medical history can be a challenge in these patients because they are often so guarded. They won’t disclose that they’ve already seen other health care providers, or that they’ve been self-treating with OTC veterinary medicine products, such as high-dose topical or oral ivermectin. They’ll often even deny repeated scratching despite clear evidence to the contrary from the skin exam.
As a dermatologist, Dr. Norton considers his first task to be a search for evidence of an infestation. Scabies is usually the first diagnosis proposed to account for the uncomfortable skin sensations. The presentation can be subtle. While the classic teaching is that the telltale signs of infestation by Sarcoptes scabiei are burrows in the skin and a rash in the web spaces between the fingers, he finds these features are often absent or equivocal.
“I think there are two more reliable presentations of scabies: Check to see if there’s symmetric involvement of the volar or palm side of the wrists; if there isn’t, I’m skeptical of the diagnosis. And every male older than 1 year of age with scabies will have scabies nodules on their genitalia. If the penis, the glans, or the scrotum aren’t involved with the nodules, I discard scabies as a possible diagnosis and look for evidence of other skin conditions that can plausibly explain the sensations and skin lesions, like eczema, contact dermatitis, scalp folliculitis, or dry skin,” he said.
If he can’t find evidence of infestation, he next systematically looks for another dermatologic cause of the patient’s sensations. When that proves fruitless, he tries to determine if there might be a biomedical or neuropsychiatric cause, such as depression, anxiety, schizophrenia, or dementia.
Taking a personal hygiene history is helpful. Patients who believe they have an infestation may bathe or shower three to five times daily with harsh soaps, causing dry, inflamed, itchy and uncomfortable skin.
“Many patients are thrilled to hear the good news that the history, physical examination, and lab tests do not show an infestation and that we have another explanation to account for their unwanted sensations. However, there are some patients who vehemently reject that idea and immediately return to their unwavering, unalterable belief that they are in fact infested. At this point, the possible diagnosis of DI looms large,” the dermatologist said.
Clues suggestive of DI include a patient’s obsessive focus on collecting “specimens” of the offending pathogen in Ziplock bags for assessment during the office visit – “usually a mix of unhelpful household debris and environmental detritus” – and eager presentation of a lengthy and detailed infestation diary, Dr. Norton said.
“Among the most distinctive signs that the patient is detached from reality are the biologically implausible descriptions and explanations of the supposed attacking organism. It’s a fanciful amalgamation of mutable features, behaviors, and life cycles composed of a composite of taxonomically unrelated organisms – for example, fungal hyphae with wings – that shapeshift at will to evade detection,” he said.
Dr. Elston observed that DI skin lesions are typically excoriated, sometimes because of a patient’s systematic use of a sharp object in an effort to dig out the infestation.
“One of the clues is the angularity of the lesion,” the dermatologist noted. “We always say round-to-oval lesions suggest an inside job; angulated lesions suggest an outside job, like fingernail work. There’s often a row of good healing border showing there’s really nothing wrong with wound healing, but a fibrinoid base where the excoriations have occurred. And the lesions are often in various stages of healing.”
Don’t forget neuropathic itch in nondelusional individuals as a potential cause of sensations of infestation and self-injury due to relentless scratching, urged Anne Louise Oaklander, MD, PhD, associate professor of neurology, Harvard Medical School, Boston, who is director of the nerve unit and the neurodiagnostic skin biopsy lab at Massachusetts General Hospital, Boston.
Dr. Anne Louise Oaklander
“There’s no one cause of patients’ impressions that they may have insects. Let’s be sympathetic: It is a normal assumption that insects may be present if the skin itches. One problem is that when patients don’t get good medical diagnoses they make up their own explanations, and sometimes these include persistent ideas of infestation. Many of them don’t realize that their scratching is a cause, not a result, of their skin lesions,” said Dr. Oaklander, who has conducted pioneering research on unintentional self-injury due to neuropathic itch accompanied by loss of pain signaling.
“Rapport first, medication later”
“The office visits are typically difficult to conclude, but skills can be learned and make it much easier to help these people,” Dr. Elston said.
John Koo, MD, emphasized that establishing rapport is “by far” the most important part of managing patients with DI.
Dr. John Koo
“Rapport first, medication later. This may require multiple visits,” said Dr. Koo, professor of dermatology at the University of California, San Francisco, who is a board-certified psychiatrist.
He makes sure he walks into the examination room all smiles and positivity. Patients with DI are eager to expound on their ailment; he lets them talk for a while, then when the timing is right, he actively encourages them to shift their focus away from etiology to treatment.
Dr. Koo and coworkers have described a spectrum of mental fixation in DI ranging from having only crawling and biting sensations, progressing to holding an overvalued idea as to their cause, then on to DSM-5 somatic preoccupation, followed by becoming truly delusional, and finally terminal delusion, where the patient doesn’t care about getting better, but only wants the physician to agree there is an infestation (J Clin Exp Dermatol Res. 2014 Oct. 3. doi: 10.4172/2155-9554.1000241).
“You cannot argue with people with delusions. How you talk to them as a clinician depends on whether they are entirely delusional or not,” he advised. “I cannot agree with their ideation, but I can agree with their misery – and that’s how I make a connection.”
Declining a DI patient’s request for a skin biopsy when it’s obvious there is no infestation can lead to a counterproductive power struggle. Instead, Dr. Koo turns the patient request into an opportunity to form a verbal contract: “I ask, ‘If the result comes back negative, can you be open-minded about the possibility of other etiologies besides parasites?’ ”
As for Dr. Norton, when his schedule shows a patient is coming in for a first visit for a supposed skin infestation, he tells his staff to expect a lengthy session as he works at establishing a good relationship.
“When my patients arrive with bags of specimens, I ask them to select two or three that they’re most confident will have a creature in them. Then I bring a two-headed microscope into the exam room and ask the patient to join me in examining the material. It helps with rapport by showing that I genuinely want to determine if there’s an infestation,” he explained.
He then sends the specimens to a laboratory, which provides a full report of the findings.
In performing a skin biopsy in a patient with suspected DI, Dr. Norton routinely biopsies two sites so the patient can’t claim sampling error when the pathology report comes back with no pathogens or parasites found. Also, he asks the patient to choose biopsy sites with intact skin where he or she believes the infestation exists. There is no point in biopsying excoriated lesions because they often contain snagged textile fibers.
Another rapport-building strategy: “I try to design a treatment regimen that will palliate the uncomfortable sensations and help relieve the patient’s misery while we continue working towards treating those delusions,” Dr. Norton said.
This might entail cutting back to one lukewarm shower per day with gentle or no soap, coupled with moisturizing, oral antihistamines or doxepin for itch, topical corticosteroids for the associated inflammation, and oral or topical antibiotics for any secondary bacterial skin infection.
What he doesn’t recommend as a rapport-building strategy or simply in order to get the patient out of the office is offering a therapeutic trial of an antiparasitic agent. That’s counterproductive. It may reinforce the false belief of infestation, and when the medication doesn’t bring lasting belief, the patient may conclude the infestation is resistant to conventional treatment.
Dr. Koo tells affected patients that he suspects they have Morgellons syndrome. He doesn’t call it DI in their presence.
“These people would not like their condition to be called delusional,” he explained. “Morgellons is a more neutral term. I tell them it’s a mysterious condition, and that what I’m really interested in is in trying to get them out of their misery.”
Treatment tips
Dr. Koo’s first-line medication for DI is pimozide (Orap), which in the United States has the advantage of being approved only for Tourette syndrome; it’s an antipsychotic without the perceived stigma of a psychiatric indication.
“Many of these patients will not consider taking any medication that has any psychiatric indication,” he noted.
Low-dose pimozide is highly effective, according to Dr. Koo, who recommends starting at 0.5 mg to 1 mg/day, increasing by 0.5 mg/day every 2-4 weeks. The drug is usually effective at a dose of 3 mg/day or less. Once a patient’s symptoms become clear or almost clear, the patient is maintained on that dose for another 3-4 months, then tapered by 0.5 mg/day every 2-4 weeks.
“In 35 years of seeing a new patient on average every week or two, I’ve had only five patients with one recurrence and one patient with two recurrences. All six responded to repeat therapy,” Dr. Koo said.
Side effects at these low doses are “very rare,” he added. Diphenhydramine (Benadryl) at 25 mg up to four times daily is effective for complaints of stiffness or restlessness. Prolongation of the QT interval is a potential concern, but Dr. Koo has never encountered it despite routinely ordering ECGs for patients on pimozide with known heart disease or who are over age 50.
When a patient can’t tolerate pimozide, Dr. Koo’s second-line antipsychotic for DI is low-dose risperidone (Risperdal), which is also highly effective.
Dr. Lepping noted that the European situation is different. There, unlike in the United States, pimozide has regulatory approval as an antipsychotic, so it loses the advantage of being an under-the-radar neuroleptic. His go-to medication is the first-generation antipsychotic sulpiride (Dogmatil), which he finds has a more favorable side effect profile than pimozide, particularly in the elderly. (Sulpiride is not approved in the United States.)
In treating DI, he prefers more dopaminergic-focused antipsychotics over those covering a broader spectrum of receptors. His alternatives to sulpiride include risperidone and olanzapine, atypical antipsychotics. He explains to patients that just as aspirin is used in low doses for its antiplatelet effect and in higher doses for pain relief, these medications can help them feel better at much lower doses than for schizophrenia.
“Once we get some rapport and a trusting relationship going, we normally try to persuade people to basically try something against their better judgment. We know that they don’t believe in it, but you try to get them to at least try something because everything else has failed,” Dr. Lepping explained. “We tell them it’s a condition we have seen before, and we have seen these medications to be useful because they are good for their distress, they help with making them calmer, and they might help with their symptoms. We say, ‘What do you have to lose if you trust us?’
“About 60% of our patients take the medication and almost invariably they all get better,” the psychiatrist said. “The others we either lose to follow-up or they just refuse to take the medication.”
A patient’s first visit to the Liverpool multispecialty DI referral clinic is 1 hour long. “They know that in advance, and we very much stick to that hour. We say to people up front, ‘We have an hour – that’s a lot, but we don’t have more,’ ” he said.
The initial visit is typically followed by two to four 30-minute follow-up visits. Dr. Lepping recommends that when possible, patients with DI should be seen jointly by a psychiatrist and a nonpsychiatrist physician. He finds this approach leads to substantially better clinical outcomes than with a single health care provider.
“If you have two people in the clinic with the patient, when you get really annoyed and your amygdala really starts going, that’s the time when you can then turn to your colleague and say, ‘Oh yes, and Professor Squire, what do you have to say to that?’ So as you see the red mist rising in yourself because you’re getting so exasperated, you have the other person there to take over so you can calm down. And then the other person does the same. That can be really important to deescalate a heated situation,” Dr. Lepping explained.
Roughly 10% of patients with DI have what is termed folie à deux, where the delusion of infestation is shared by another person.
“Anecdotally, I would say those are much more difficult to treat,” said Jason S. Reichenberg, MD, MBA, professor of medicine (dermatology) at the University of Texas at Austin and president of the Ascension Medical Group Texas.
Dr. Jason S. Reichenberg
“It’s like getting somebody to quit smoking when everybody else in the house is still smoking. It’s very hard to convince a single family member that they’re wrong when everybody else in their family keeps telling them they’re right,” he said.
Recent advances in DI research
Dr. Lepping and coinvestigators at multispecialist DI clinics in London, Italy, and Moscow reported in an unusually large observational study of 236 affected patients that longer duration of untreated psychosis was associated with significantly worse clinical outcome. It’s a finding consistent with Dr. Koo’s construct of progressive stages of delusionality, and it underscores the need for early treatment.
“Having said that, improvement is still possible, even if people have had quite a long time of untreated psychosis,” Dr. Lepping said. The same study also showed that older age at illness onset was inversely associated with good outcome.
In another study, Dr. Lepping and colleagues reported that substance use involving amphetamines, cocaine, opioids, and other drugs that can cause itch was roughly twice as common in a group of patients with DI compared to the general population. “I highly recommend, if at all possible, a drug screen in suspected DI,” he said.
In a large survey of U.S. and Canadian veterinarians, Dr. Lepping and coinvestigators found that these practitioners not infrequently encountered delusional infestation among pet owners who claimed their dog or cat is infested when it’s not. This is called “delusion by proxy,” and it often leads to unwarranted animal euthanasia. Some of these pet owners claim they, too, are infested, which the investigators termed “double delusional infestation.”
MRI studies
Recent structural brain MRI studies support the concept that impaired somatosensory neural networks mediate the delusional symptoms of DI, but not in delusional disorders without somatic content. This was demonstrated in an MRI study by Dr. Lepping and others conducted in 18 patients with DI, 19 others with nonsomatic delusional disorders centered on themes of persecution or jealousy, and 20 healthy volunteers. The DI group had lower gray matter volume in prefrontal, thalamic, striatal, and insular regions of the brain compared to the other two groups.
Of note, mapping of the insula and dorsal striatum indicates they are part of the peripersonal space network, which integrates tactile and visual perceptions involving the area near the body surface. The insula also mediates feelings of pain and disgust.
Some of the same investigators have also recently reported brain MRI evidence specifically of cerebellar dysfunction in patients with DI, who displayed decreased gray matter volume in left lobule VIIa of the cerebellum and increased gray matter volume in bilateral lobule VIIa/crus II compared to patients with non-somatic delusions. This points to a role for impaired cerebellar neural networks related to somatosensory perception in patients with DI but not in those with non-somatic delusions.
Delusional infestation: What’s in a name?
Ekbom syndrome. Delusional parasitosis. Morgellons syndrome. These and other terms are increasingly giving way to ‘delusional infestation’ as the preferred moniker for the disorder. That’s in part because the delusional focus in patients with this condition has shifted over time. In the 19th century, for example, affected patients often attributed their infestation to typhus.
In contemporary practice, roughly one-quarter of affected patients think they are infested by small inanimate objects, most commonly fibers or threads emerging from the skin, rather than by parasites, insects, or worms. In a study of 148 consecutive European patients with suspected DI, Dr. Lepping and coinvestigators reported only 35% believed they were infested by parasites.
“The name ‘delusional infestation’ emphasizes the constantly changing pathogens and covers all present and future variations of the theme that are bound to occur,” Dr. Lepping observed.
All speakers reported having no conflicts of interest.
Psychiatrists with expertise in delusional infestation have some advice for dermatologists, infectious disease specialists, and primary care physicians who encounter affected patients: If you want to try to help them, initiate treatment yourself.
Dr. Peter Lepping
“If you see it, try and treat it. These patients are unlikely to agree to see a psychiatrist,” Peter Lepping, MD, said at the Entomology 2020 annual meeting.
Indeed, one of the hallmarks of delusional infestation (DI) is a refusal to even consider referral to a mental health professional, noted Dr. Lepping, a consultation-liaison psychiatrist at Bangor (Wales) University who, together with an infectious disease specialist, codirects one of the world’s few DI multispecialty referral clinics, located at the University of Liverpool School of Tropical Medicine.
That being said, he offered another piece of advice: “Accept that it is not easy to help these patients.”
Dr. Lepping was among a group of distinguished psychiatrists, dermatologists, entomologists, and a neurologist at the annual meeting who participated in a comprehensive session devoted to DI. The experts shared tips on making the diagnosis, establishing the rapport necessary to persuade affected patients to try taking a very-low-dose antipsychotic agent for their delusion, and how to achieve a high rate of therapeutic success. They also highlighted recent research advances in the field, including brain MRI evidence suggesting that impaired somatosensory neural networks mediate symptoms in DI, but not in nonsomatic delusional disorders.
COVID-19 pandemic triggers surge in DI
Entomologist Gail E. Ridge, PhD, has taken notes on all of her thousands of consultations with individuals with suspected DI since the late 1990s. A sharp jump in such contacts occurred during the Great Recession of 2008 in conjunction with the widespread social distress of job loss and threatened economic ruin. Now the same thing is happening as the catastrophic COVID-19 pandemic stretches on. Indeed, during the first 8 months of the pandemic she documented 500 interactions involving people with suspected DI. She’s learned to identify the clues, including a chattering mind, defensiveness, physician avoidance, and rigid body tension.
Courtesy Dr. Gale E. Ridge
Dr. Gale E. Ridge
“They’re fearful of judgment and suggestions of madness. And they’ll pounce on any perceived negativity. I never debunk beliefs; that can immediately backfire. If the medical profession was educated about DI, then many cases could be caught early. I, as the entomologist, and the mental health professionals are often last in line to be seen,” said Dr. Ridge, director of the Insect Information Office at the Connecticut Agricultural Experiment Station in New Haven.
She has noticed a recurring theme in her interactions with these patients: DI often starts with a real underlying medical condition, such as, for example, a cutaneous drug reaction, which over time, progresses to gain a psychiatric component. And she has found that a tipping point often occurs after roughly 6 months of unrelieved symptoms and sensations. Prior to that, affected individuals are concerned about their condition and will seek medical help in a genuine effort to understand what’s going on. They can be redirected. After about 6 months, however, Dr. Ridge has observed “they slide into the rabbit hole of fanaticism and despair.”
Arriving at the diagnosis
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), DI is classified as a “delusional disorder, somatic type 297.1 F22.” The diagnosis requires that the delusion be present for at least 1 month, criteria for schizophrenia are not met, and the condition cannot be attributed to other medical or neuropsychiatric conditions.
“Many of these people are very high-functioning. I have corporate CEOs who fly in to see me in their private jets. At work, they’re king of their domain. At home, their family is falling apart because of their delusion,” said Dirk M. Elston, MD, professor and chair of the department of dermatology and dermatologic surgery at the Medical University of South Carolina, Charleston.
Dr. Dirk M. Elston
“These people suffer, and the people around them suffer,” he emphasized.
Dozens of medical conditions can cause intractable itching or biting sensations. Far and away at the top of the medical differential diagnosis is thyroid disease, given its high incidence and frequent presentation with anxiety and itch. Other possibilities that can readily be ruled out via lab tests include substance use – especially involving amphetamine/methamphetamine, cocaine, or opioids – liver or kidney disease, diabetes and other sources of peripheral neuropathy, polycythemia, dermatitis herpetiformis, and pemphigus, Dr. Elston said.
Scott A. Norton, MD, MPH, MSc, a dermatologist and preventive medicine specialist at the Uniformed Services University of the Health Sciences in Bethesda, Md., noted that a diagnosis of DI requires three elements: The presence of abnormal sensations in the skin, a patient’s tenacious conviction that the sensations are caused by an infestation, and a lack of supporting evidence for that conviction.
Dr. Scott A. Norton
Taking an accurate medical history can be a challenge in these patients because they are often so guarded. They won’t disclose that they’ve already seen other health care providers, or that they’ve been self-treating with OTC veterinary medicine products, such as high-dose topical or oral ivermectin. They’ll often even deny repeated scratching despite clear evidence to the contrary from the skin exam.
As a dermatologist, Dr. Norton considers his first task to be a search for evidence of an infestation. Scabies is usually the first diagnosis proposed to account for the uncomfortable skin sensations. The presentation can be subtle. While the classic teaching is that the telltale signs of infestation by Sarcoptes scabiei are burrows in the skin and a rash in the web spaces between the fingers, he finds these features are often absent or equivocal.
“I think there are two more reliable presentations of scabies: Check to see if there’s symmetric involvement of the volar or palm side of the wrists; if there isn’t, I’m skeptical of the diagnosis. And every male older than 1 year of age with scabies will have scabies nodules on their genitalia. If the penis, the glans, or the scrotum aren’t involved with the nodules, I discard scabies as a possible diagnosis and look for evidence of other skin conditions that can plausibly explain the sensations and skin lesions, like eczema, contact dermatitis, scalp folliculitis, or dry skin,” he said.
If he can’t find evidence of infestation, he next systematically looks for another dermatologic cause of the patient’s sensations. When that proves fruitless, he tries to determine if there might be a biomedical or neuropsychiatric cause, such as depression, anxiety, schizophrenia, or dementia.
Taking a personal hygiene history is helpful. Patients who believe they have an infestation may bathe or shower three to five times daily with harsh soaps, causing dry, inflamed, itchy and uncomfortable skin.
“Many patients are thrilled to hear the good news that the history, physical examination, and lab tests do not show an infestation and that we have another explanation to account for their unwanted sensations. However, there are some patients who vehemently reject that idea and immediately return to their unwavering, unalterable belief that they are in fact infested. At this point, the possible diagnosis of DI looms large,” the dermatologist said.
Clues suggestive of DI include a patient’s obsessive focus on collecting “specimens” of the offending pathogen in Ziplock bags for assessment during the office visit – “usually a mix of unhelpful household debris and environmental detritus” – and eager presentation of a lengthy and detailed infestation diary, Dr. Norton said.
“Among the most distinctive signs that the patient is detached from reality are the biologically implausible descriptions and explanations of the supposed attacking organism. It’s a fanciful amalgamation of mutable features, behaviors, and life cycles composed of a composite of taxonomically unrelated organisms – for example, fungal hyphae with wings – that shapeshift at will to evade detection,” he said.
Dr. Elston observed that DI skin lesions are typically excoriated, sometimes because of a patient’s systematic use of a sharp object in an effort to dig out the infestation.
“One of the clues is the angularity of the lesion,” the dermatologist noted. “We always say round-to-oval lesions suggest an inside job; angulated lesions suggest an outside job, like fingernail work. There’s often a row of good healing border showing there’s really nothing wrong with wound healing, but a fibrinoid base where the excoriations have occurred. And the lesions are often in various stages of healing.”
Don’t forget neuropathic itch in nondelusional individuals as a potential cause of sensations of infestation and self-injury due to relentless scratching, urged Anne Louise Oaklander, MD, PhD, associate professor of neurology, Harvard Medical School, Boston, who is director of the nerve unit and the neurodiagnostic skin biopsy lab at Massachusetts General Hospital, Boston.
Dr. Anne Louise Oaklander
“There’s no one cause of patients’ impressions that they may have insects. Let’s be sympathetic: It is a normal assumption that insects may be present if the skin itches. One problem is that when patients don’t get good medical diagnoses they make up their own explanations, and sometimes these include persistent ideas of infestation. Many of them don’t realize that their scratching is a cause, not a result, of their skin lesions,” said Dr. Oaklander, who has conducted pioneering research on unintentional self-injury due to neuropathic itch accompanied by loss of pain signaling.
“Rapport first, medication later”
“The office visits are typically difficult to conclude, but skills can be learned and make it much easier to help these people,” Dr. Elston said.
John Koo, MD, emphasized that establishing rapport is “by far” the most important part of managing patients with DI.
Dr. John Koo
“Rapport first, medication later. This may require multiple visits,” said Dr. Koo, professor of dermatology at the University of California, San Francisco, who is a board-certified psychiatrist.
He makes sure he walks into the examination room all smiles and positivity. Patients with DI are eager to expound on their ailment; he lets them talk for a while, then when the timing is right, he actively encourages them to shift their focus away from etiology to treatment.
Dr. Koo and coworkers have described a spectrum of mental fixation in DI ranging from having only crawling and biting sensations, progressing to holding an overvalued idea as to their cause, then on to DSM-5 somatic preoccupation, followed by becoming truly delusional, and finally terminal delusion, where the patient doesn’t care about getting better, but only wants the physician to agree there is an infestation (J Clin Exp Dermatol Res. 2014 Oct. 3. doi: 10.4172/2155-9554.1000241).
“You cannot argue with people with delusions. How you talk to them as a clinician depends on whether they are entirely delusional or not,” he advised. “I cannot agree with their ideation, but I can agree with their misery – and that’s how I make a connection.”
Declining a DI patient’s request for a skin biopsy when it’s obvious there is no infestation can lead to a counterproductive power struggle. Instead, Dr. Koo turns the patient request into an opportunity to form a verbal contract: “I ask, ‘If the result comes back negative, can you be open-minded about the possibility of other etiologies besides parasites?’ ”
As for Dr. Norton, when his schedule shows a patient is coming in for a first visit for a supposed skin infestation, he tells his staff to expect a lengthy session as he works at establishing a good relationship.
“When my patients arrive with bags of specimens, I ask them to select two or three that they’re most confident will have a creature in them. Then I bring a two-headed microscope into the exam room and ask the patient to join me in examining the material. It helps with rapport by showing that I genuinely want to determine if there’s an infestation,” he explained.
He then sends the specimens to a laboratory, which provides a full report of the findings.
In performing a skin biopsy in a patient with suspected DI, Dr. Norton routinely biopsies two sites so the patient can’t claim sampling error when the pathology report comes back with no pathogens or parasites found. Also, he asks the patient to choose biopsy sites with intact skin where he or she believes the infestation exists. There is no point in biopsying excoriated lesions because they often contain snagged textile fibers.
Another rapport-building strategy: “I try to design a treatment regimen that will palliate the uncomfortable sensations and help relieve the patient’s misery while we continue working towards treating those delusions,” Dr. Norton said.
This might entail cutting back to one lukewarm shower per day with gentle or no soap, coupled with moisturizing, oral antihistamines or doxepin for itch, topical corticosteroids for the associated inflammation, and oral or topical antibiotics for any secondary bacterial skin infection.
What he doesn’t recommend as a rapport-building strategy or simply in order to get the patient out of the office is offering a therapeutic trial of an antiparasitic agent. That’s counterproductive. It may reinforce the false belief of infestation, and when the medication doesn’t bring lasting belief, the patient may conclude the infestation is resistant to conventional treatment.
Dr. Koo tells affected patients that he suspects they have Morgellons syndrome. He doesn’t call it DI in their presence.
“These people would not like their condition to be called delusional,” he explained. “Morgellons is a more neutral term. I tell them it’s a mysterious condition, and that what I’m really interested in is in trying to get them out of their misery.”
Treatment tips
Dr. Koo’s first-line medication for DI is pimozide (Orap), which in the United States has the advantage of being approved only for Tourette syndrome; it’s an antipsychotic without the perceived stigma of a psychiatric indication.
“Many of these patients will not consider taking any medication that has any psychiatric indication,” he noted.
Low-dose pimozide is highly effective, according to Dr. Koo, who recommends starting at 0.5 mg to 1 mg/day, increasing by 0.5 mg/day every 2-4 weeks. The drug is usually effective at a dose of 3 mg/day or less. Once a patient’s symptoms become clear or almost clear, the patient is maintained on that dose for another 3-4 months, then tapered by 0.5 mg/day every 2-4 weeks.
“In 35 years of seeing a new patient on average every week or two, I’ve had only five patients with one recurrence and one patient with two recurrences. All six responded to repeat therapy,” Dr. Koo said.
Side effects at these low doses are “very rare,” he added. Diphenhydramine (Benadryl) at 25 mg up to four times daily is effective for complaints of stiffness or restlessness. Prolongation of the QT interval is a potential concern, but Dr. Koo has never encountered it despite routinely ordering ECGs for patients on pimozide with known heart disease or who are over age 50.
When a patient can’t tolerate pimozide, Dr. Koo’s second-line antipsychotic for DI is low-dose risperidone (Risperdal), which is also highly effective.
Dr. Lepping noted that the European situation is different. There, unlike in the United States, pimozide has regulatory approval as an antipsychotic, so it loses the advantage of being an under-the-radar neuroleptic. His go-to medication is the first-generation antipsychotic sulpiride (Dogmatil), which he finds has a more favorable side effect profile than pimozide, particularly in the elderly. (Sulpiride is not approved in the United States.)
In treating DI, he prefers more dopaminergic-focused antipsychotics over those covering a broader spectrum of receptors. His alternatives to sulpiride include risperidone and olanzapine, atypical antipsychotics. He explains to patients that just as aspirin is used in low doses for its antiplatelet effect and in higher doses for pain relief, these medications can help them feel better at much lower doses than for schizophrenia.
“Once we get some rapport and a trusting relationship going, we normally try to persuade people to basically try something against their better judgment. We know that they don’t believe in it, but you try to get them to at least try something because everything else has failed,” Dr. Lepping explained. “We tell them it’s a condition we have seen before, and we have seen these medications to be useful because they are good for their distress, they help with making them calmer, and they might help with their symptoms. We say, ‘What do you have to lose if you trust us?’
“About 60% of our patients take the medication and almost invariably they all get better,” the psychiatrist said. “The others we either lose to follow-up or they just refuse to take the medication.”
A patient’s first visit to the Liverpool multispecialty DI referral clinic is 1 hour long. “They know that in advance, and we very much stick to that hour. We say to people up front, ‘We have an hour – that’s a lot, but we don’t have more,’ ” he said.
The initial visit is typically followed by two to four 30-minute follow-up visits. Dr. Lepping recommends that when possible, patients with DI should be seen jointly by a psychiatrist and a nonpsychiatrist physician. He finds this approach leads to substantially better clinical outcomes than with a single health care provider.
“If you have two people in the clinic with the patient, when you get really annoyed and your amygdala really starts going, that’s the time when you can then turn to your colleague and say, ‘Oh yes, and Professor Squire, what do you have to say to that?’ So as you see the red mist rising in yourself because you’re getting so exasperated, you have the other person there to take over so you can calm down. And then the other person does the same. That can be really important to deescalate a heated situation,” Dr. Lepping explained.
Roughly 10% of patients with DI have what is termed folie à deux, where the delusion of infestation is shared by another person.
“Anecdotally, I would say those are much more difficult to treat,” said Jason S. Reichenberg, MD, MBA, professor of medicine (dermatology) at the University of Texas at Austin and president of the Ascension Medical Group Texas.
Dr. Jason S. Reichenberg
“It’s like getting somebody to quit smoking when everybody else in the house is still smoking. It’s very hard to convince a single family member that they’re wrong when everybody else in their family keeps telling them they’re right,” he said.
Recent advances in DI research
Dr. Lepping and coinvestigators at multispecialist DI clinics in London, Italy, and Moscow reported in an unusually large observational study of 236 affected patients that longer duration of untreated psychosis was associated with significantly worse clinical outcome. It’s a finding consistent with Dr. Koo’s construct of progressive stages of delusionality, and it underscores the need for early treatment.
“Having said that, improvement is still possible, even if people have had quite a long time of untreated psychosis,” Dr. Lepping said. The same study also showed that older age at illness onset was inversely associated with good outcome.
In another study, Dr. Lepping and colleagues reported that substance use involving amphetamines, cocaine, opioids, and other drugs that can cause itch was roughly twice as common in a group of patients with DI compared to the general population. “I highly recommend, if at all possible, a drug screen in suspected DI,” he said.
In a large survey of U.S. and Canadian veterinarians, Dr. Lepping and coinvestigators found that these practitioners not infrequently encountered delusional infestation among pet owners who claimed their dog or cat is infested when it’s not. This is called “delusion by proxy,” and it often leads to unwarranted animal euthanasia. Some of these pet owners claim they, too, are infested, which the investigators termed “double delusional infestation.”
MRI studies
Recent structural brain MRI studies support the concept that impaired somatosensory neural networks mediate the delusional symptoms of DI, but not in delusional disorders without somatic content. This was demonstrated in an MRI study by Dr. Lepping and others conducted in 18 patients with DI, 19 others with nonsomatic delusional disorders centered on themes of persecution or jealousy, and 20 healthy volunteers. The DI group had lower gray matter volume in prefrontal, thalamic, striatal, and insular regions of the brain compared to the other two groups.
Of note, mapping of the insula and dorsal striatum indicates they are part of the peripersonal space network, which integrates tactile and visual perceptions involving the area near the body surface. The insula also mediates feelings of pain and disgust.
Some of the same investigators have also recently reported brain MRI evidence specifically of cerebellar dysfunction in patients with DI, who displayed decreased gray matter volume in left lobule VIIa of the cerebellum and increased gray matter volume in bilateral lobule VIIa/crus II compared to patients with non-somatic delusions. This points to a role for impaired cerebellar neural networks related to somatosensory perception in patients with DI but not in those with non-somatic delusions.
Delusional infestation: What’s in a name?
Ekbom syndrome. Delusional parasitosis. Morgellons syndrome. These and other terms are increasingly giving way to ‘delusional infestation’ as the preferred moniker for the disorder. That’s in part because the delusional focus in patients with this condition has shifted over time. In the 19th century, for example, affected patients often attributed their infestation to typhus.
In contemporary practice, roughly one-quarter of affected patients think they are infested by small inanimate objects, most commonly fibers or threads emerging from the skin, rather than by parasites, insects, or worms. In a study of 148 consecutive European patients with suspected DI, Dr. Lepping and coinvestigators reported only 35% believed they were infested by parasites.
“The name ‘delusional infestation’ emphasizes the constantly changing pathogens and covers all present and future variations of the theme that are bound to occur,” Dr. Lepping observed.
All speakers reported having no conflicts of interest.
Psychiatrists with expertise in delusional infestation have some advice for dermatologists, infectious disease specialists, and primary care physicians who encounter affected patients: If you want to try to help them, initiate treatment yourself.
Dr. Peter Lepping
“If you see it, try and treat it. These patients are unlikely to agree to see a psychiatrist,” Peter Lepping, MD, said at the Entomology 2020 annual meeting.
Indeed, one of the hallmarks of delusional infestation (DI) is a refusal to even consider referral to a mental health professional, noted Dr. Lepping, a consultation-liaison psychiatrist at Bangor (Wales) University who, together with an infectious disease specialist, codirects one of the world’s few DI multispecialty referral clinics, located at the University of Liverpool School of Tropical Medicine.
That being said, he offered another piece of advice: “Accept that it is not easy to help these patients.”
Dr. Lepping was among a group of distinguished psychiatrists, dermatologists, entomologists, and a neurologist at the annual meeting who participated in a comprehensive session devoted to DI. The experts shared tips on making the diagnosis, establishing the rapport necessary to persuade affected patients to try taking a very-low-dose antipsychotic agent for their delusion, and how to achieve a high rate of therapeutic success. They also highlighted recent research advances in the field, including brain MRI evidence suggesting that impaired somatosensory neural networks mediate symptoms in DI, but not in nonsomatic delusional disorders.
COVID-19 pandemic triggers surge in DI
Entomologist Gail E. Ridge, PhD, has taken notes on all of her thousands of consultations with individuals with suspected DI since the late 1990s. A sharp jump in such contacts occurred during the Great Recession of 2008 in conjunction with the widespread social distress of job loss and threatened economic ruin. Now the same thing is happening as the catastrophic COVID-19 pandemic stretches on. Indeed, during the first 8 months of the pandemic she documented 500 interactions involving people with suspected DI. She’s learned to identify the clues, including a chattering mind, defensiveness, physician avoidance, and rigid body tension.
Courtesy Dr. Gale E. Ridge
Dr. Gale E. Ridge
“They’re fearful of judgment and suggestions of madness. And they’ll pounce on any perceived negativity. I never debunk beliefs; that can immediately backfire. If the medical profession was educated about DI, then many cases could be caught early. I, as the entomologist, and the mental health professionals are often last in line to be seen,” said Dr. Ridge, director of the Insect Information Office at the Connecticut Agricultural Experiment Station in New Haven.
She has noticed a recurring theme in her interactions with these patients: DI often starts with a real underlying medical condition, such as, for example, a cutaneous drug reaction, which over time, progresses to gain a psychiatric component. And she has found that a tipping point often occurs after roughly 6 months of unrelieved symptoms and sensations. Prior to that, affected individuals are concerned about their condition and will seek medical help in a genuine effort to understand what’s going on. They can be redirected. After about 6 months, however, Dr. Ridge has observed “they slide into the rabbit hole of fanaticism and despair.”
Arriving at the diagnosis
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), DI is classified as a “delusional disorder, somatic type 297.1 F22.” The diagnosis requires that the delusion be present for at least 1 month, criteria for schizophrenia are not met, and the condition cannot be attributed to other medical or neuropsychiatric conditions.
“Many of these people are very high-functioning. I have corporate CEOs who fly in to see me in their private jets. At work, they’re king of their domain. At home, their family is falling apart because of their delusion,” said Dirk M. Elston, MD, professor and chair of the department of dermatology and dermatologic surgery at the Medical University of South Carolina, Charleston.
Dr. Dirk M. Elston
“These people suffer, and the people around them suffer,” he emphasized.
Dozens of medical conditions can cause intractable itching or biting sensations. Far and away at the top of the medical differential diagnosis is thyroid disease, given its high incidence and frequent presentation with anxiety and itch. Other possibilities that can readily be ruled out via lab tests include substance use – especially involving amphetamine/methamphetamine, cocaine, or opioids – liver or kidney disease, diabetes and other sources of peripheral neuropathy, polycythemia, dermatitis herpetiformis, and pemphigus, Dr. Elston said.
Scott A. Norton, MD, MPH, MSc, a dermatologist and preventive medicine specialist at the Uniformed Services University of the Health Sciences in Bethesda, Md., noted that a diagnosis of DI requires three elements: The presence of abnormal sensations in the skin, a patient’s tenacious conviction that the sensations are caused by an infestation, and a lack of supporting evidence for that conviction.
Dr. Scott A. Norton
Taking an accurate medical history can be a challenge in these patients because they are often so guarded. They won’t disclose that they’ve already seen other health care providers, or that they’ve been self-treating with OTC veterinary medicine products, such as high-dose topical or oral ivermectin. They’ll often even deny repeated scratching despite clear evidence to the contrary from the skin exam.
As a dermatologist, Dr. Norton considers his first task to be a search for evidence of an infestation. Scabies is usually the first diagnosis proposed to account for the uncomfortable skin sensations. The presentation can be subtle. While the classic teaching is that the telltale signs of infestation by Sarcoptes scabiei are burrows in the skin and a rash in the web spaces between the fingers, he finds these features are often absent or equivocal.
“I think there are two more reliable presentations of scabies: Check to see if there’s symmetric involvement of the volar or palm side of the wrists; if there isn’t, I’m skeptical of the diagnosis. And every male older than 1 year of age with scabies will have scabies nodules on their genitalia. If the penis, the glans, or the scrotum aren’t involved with the nodules, I discard scabies as a possible diagnosis and look for evidence of other skin conditions that can plausibly explain the sensations and skin lesions, like eczema, contact dermatitis, scalp folliculitis, or dry skin,” he said.
If he can’t find evidence of infestation, he next systematically looks for another dermatologic cause of the patient’s sensations. When that proves fruitless, he tries to determine if there might be a biomedical or neuropsychiatric cause, such as depression, anxiety, schizophrenia, or dementia.
Taking a personal hygiene history is helpful. Patients who believe they have an infestation may bathe or shower three to five times daily with harsh soaps, causing dry, inflamed, itchy and uncomfortable skin.
“Many patients are thrilled to hear the good news that the history, physical examination, and lab tests do not show an infestation and that we have another explanation to account for their unwanted sensations. However, there are some patients who vehemently reject that idea and immediately return to their unwavering, unalterable belief that they are in fact infested. At this point, the possible diagnosis of DI looms large,” the dermatologist said.
Clues suggestive of DI include a patient’s obsessive focus on collecting “specimens” of the offending pathogen in Ziplock bags for assessment during the office visit – “usually a mix of unhelpful household debris and environmental detritus” – and eager presentation of a lengthy and detailed infestation diary, Dr. Norton said.
“Among the most distinctive signs that the patient is detached from reality are the biologically implausible descriptions and explanations of the supposed attacking organism. It’s a fanciful amalgamation of mutable features, behaviors, and life cycles composed of a composite of taxonomically unrelated organisms – for example, fungal hyphae with wings – that shapeshift at will to evade detection,” he said.
Dr. Elston observed that DI skin lesions are typically excoriated, sometimes because of a patient’s systematic use of a sharp object in an effort to dig out the infestation.
“One of the clues is the angularity of the lesion,” the dermatologist noted. “We always say round-to-oval lesions suggest an inside job; angulated lesions suggest an outside job, like fingernail work. There’s often a row of good healing border showing there’s really nothing wrong with wound healing, but a fibrinoid base where the excoriations have occurred. And the lesions are often in various stages of healing.”
Don’t forget neuropathic itch in nondelusional individuals as a potential cause of sensations of infestation and self-injury due to relentless scratching, urged Anne Louise Oaklander, MD, PhD, associate professor of neurology, Harvard Medical School, Boston, who is director of the nerve unit and the neurodiagnostic skin biopsy lab at Massachusetts General Hospital, Boston.
Dr. Anne Louise Oaklander
“There’s no one cause of patients’ impressions that they may have insects. Let’s be sympathetic: It is a normal assumption that insects may be present if the skin itches. One problem is that when patients don’t get good medical diagnoses they make up their own explanations, and sometimes these include persistent ideas of infestation. Many of them don’t realize that their scratching is a cause, not a result, of their skin lesions,” said Dr. Oaklander, who has conducted pioneering research on unintentional self-injury due to neuropathic itch accompanied by loss of pain signaling.
“Rapport first, medication later”
“The office visits are typically difficult to conclude, but skills can be learned and make it much easier to help these people,” Dr. Elston said.
John Koo, MD, emphasized that establishing rapport is “by far” the most important part of managing patients with DI.
Dr. John Koo
“Rapport first, medication later. This may require multiple visits,” said Dr. Koo, professor of dermatology at the University of California, San Francisco, who is a board-certified psychiatrist.
He makes sure he walks into the examination room all smiles and positivity. Patients with DI are eager to expound on their ailment; he lets them talk for a while, then when the timing is right, he actively encourages them to shift their focus away from etiology to treatment.
Dr. Koo and coworkers have described a spectrum of mental fixation in DI ranging from having only crawling and biting sensations, progressing to holding an overvalued idea as to their cause, then on to DSM-5 somatic preoccupation, followed by becoming truly delusional, and finally terminal delusion, where the patient doesn’t care about getting better, but only wants the physician to agree there is an infestation (J Clin Exp Dermatol Res. 2014 Oct. 3. doi: 10.4172/2155-9554.1000241).
“You cannot argue with people with delusions. How you talk to them as a clinician depends on whether they are entirely delusional or not,” he advised. “I cannot agree with their ideation, but I can agree with their misery – and that’s how I make a connection.”
Declining a DI patient’s request for a skin biopsy when it’s obvious there is no infestation can lead to a counterproductive power struggle. Instead, Dr. Koo turns the patient request into an opportunity to form a verbal contract: “I ask, ‘If the result comes back negative, can you be open-minded about the possibility of other etiologies besides parasites?’ ”
As for Dr. Norton, when his schedule shows a patient is coming in for a first visit for a supposed skin infestation, he tells his staff to expect a lengthy session as he works at establishing a good relationship.
“When my patients arrive with bags of specimens, I ask them to select two or three that they’re most confident will have a creature in them. Then I bring a two-headed microscope into the exam room and ask the patient to join me in examining the material. It helps with rapport by showing that I genuinely want to determine if there’s an infestation,” he explained.
He then sends the specimens to a laboratory, which provides a full report of the findings.
In performing a skin biopsy in a patient with suspected DI, Dr. Norton routinely biopsies two sites so the patient can’t claim sampling error when the pathology report comes back with no pathogens or parasites found. Also, he asks the patient to choose biopsy sites with intact skin where he or she believes the infestation exists. There is no point in biopsying excoriated lesions because they often contain snagged textile fibers.
Another rapport-building strategy: “I try to design a treatment regimen that will palliate the uncomfortable sensations and help relieve the patient’s misery while we continue working towards treating those delusions,” Dr. Norton said.
This might entail cutting back to one lukewarm shower per day with gentle or no soap, coupled with moisturizing, oral antihistamines or doxepin for itch, topical corticosteroids for the associated inflammation, and oral or topical antibiotics for any secondary bacterial skin infection.
What he doesn’t recommend as a rapport-building strategy or simply in order to get the patient out of the office is offering a therapeutic trial of an antiparasitic agent. That’s counterproductive. It may reinforce the false belief of infestation, and when the medication doesn’t bring lasting belief, the patient may conclude the infestation is resistant to conventional treatment.
Dr. Koo tells affected patients that he suspects they have Morgellons syndrome. He doesn’t call it DI in their presence.
“These people would not like their condition to be called delusional,” he explained. “Morgellons is a more neutral term. I tell them it’s a mysterious condition, and that what I’m really interested in is in trying to get them out of their misery.”
Treatment tips
Dr. Koo’s first-line medication for DI is pimozide (Orap), which in the United States has the advantage of being approved only for Tourette syndrome; it’s an antipsychotic without the perceived stigma of a psychiatric indication.
“Many of these patients will not consider taking any medication that has any psychiatric indication,” he noted.
Low-dose pimozide is highly effective, according to Dr. Koo, who recommends starting at 0.5 mg to 1 mg/day, increasing by 0.5 mg/day every 2-4 weeks. The drug is usually effective at a dose of 3 mg/day or less. Once a patient’s symptoms become clear or almost clear, the patient is maintained on that dose for another 3-4 months, then tapered by 0.5 mg/day every 2-4 weeks.
“In 35 years of seeing a new patient on average every week or two, I’ve had only five patients with one recurrence and one patient with two recurrences. All six responded to repeat therapy,” Dr. Koo said.
Side effects at these low doses are “very rare,” he added. Diphenhydramine (Benadryl) at 25 mg up to four times daily is effective for complaints of stiffness or restlessness. Prolongation of the QT interval is a potential concern, but Dr. Koo has never encountered it despite routinely ordering ECGs for patients on pimozide with known heart disease or who are over age 50.
When a patient can’t tolerate pimozide, Dr. Koo’s second-line antipsychotic for DI is low-dose risperidone (Risperdal), which is also highly effective.
Dr. Lepping noted that the European situation is different. There, unlike in the United States, pimozide has regulatory approval as an antipsychotic, so it loses the advantage of being an under-the-radar neuroleptic. His go-to medication is the first-generation antipsychotic sulpiride (Dogmatil), which he finds has a more favorable side effect profile than pimozide, particularly in the elderly. (Sulpiride is not approved in the United States.)
In treating DI, he prefers more dopaminergic-focused antipsychotics over those covering a broader spectrum of receptors. His alternatives to sulpiride include risperidone and olanzapine, atypical antipsychotics. He explains to patients that just as aspirin is used in low doses for its antiplatelet effect and in higher doses for pain relief, these medications can help them feel better at much lower doses than for schizophrenia.
“Once we get some rapport and a trusting relationship going, we normally try to persuade people to basically try something against their better judgment. We know that they don’t believe in it, but you try to get them to at least try something because everything else has failed,” Dr. Lepping explained. “We tell them it’s a condition we have seen before, and we have seen these medications to be useful because they are good for their distress, they help with making them calmer, and they might help with their symptoms. We say, ‘What do you have to lose if you trust us?’
“About 60% of our patients take the medication and almost invariably they all get better,” the psychiatrist said. “The others we either lose to follow-up or they just refuse to take the medication.”
A patient’s first visit to the Liverpool multispecialty DI referral clinic is 1 hour long. “They know that in advance, and we very much stick to that hour. We say to people up front, ‘We have an hour – that’s a lot, but we don’t have more,’ ” he said.
The initial visit is typically followed by two to four 30-minute follow-up visits. Dr. Lepping recommends that when possible, patients with DI should be seen jointly by a psychiatrist and a nonpsychiatrist physician. He finds this approach leads to substantially better clinical outcomes than with a single health care provider.
“If you have two people in the clinic with the patient, when you get really annoyed and your amygdala really starts going, that’s the time when you can then turn to your colleague and say, ‘Oh yes, and Professor Squire, what do you have to say to that?’ So as you see the red mist rising in yourself because you’re getting so exasperated, you have the other person there to take over so you can calm down. And then the other person does the same. That can be really important to deescalate a heated situation,” Dr. Lepping explained.
Roughly 10% of patients with DI have what is termed folie à deux, where the delusion of infestation is shared by another person.
“Anecdotally, I would say those are much more difficult to treat,” said Jason S. Reichenberg, MD, MBA, professor of medicine (dermatology) at the University of Texas at Austin and president of the Ascension Medical Group Texas.
Dr. Jason S. Reichenberg
“It’s like getting somebody to quit smoking when everybody else in the house is still smoking. It’s very hard to convince a single family member that they’re wrong when everybody else in their family keeps telling them they’re right,” he said.
Recent advances in DI research
Dr. Lepping and coinvestigators at multispecialist DI clinics in London, Italy, and Moscow reported in an unusually large observational study of 236 affected patients that longer duration of untreated psychosis was associated with significantly worse clinical outcome. It’s a finding consistent with Dr. Koo’s construct of progressive stages of delusionality, and it underscores the need for early treatment.
“Having said that, improvement is still possible, even if people have had quite a long time of untreated psychosis,” Dr. Lepping said. The same study also showed that older age at illness onset was inversely associated with good outcome.
In another study, Dr. Lepping and colleagues reported that substance use involving amphetamines, cocaine, opioids, and other drugs that can cause itch was roughly twice as common in a group of patients with DI compared to the general population. “I highly recommend, if at all possible, a drug screen in suspected DI,” he said.
In a large survey of U.S. and Canadian veterinarians, Dr. Lepping and coinvestigators found that these practitioners not infrequently encountered delusional infestation among pet owners who claimed their dog or cat is infested when it’s not. This is called “delusion by proxy,” and it often leads to unwarranted animal euthanasia. Some of these pet owners claim they, too, are infested, which the investigators termed “double delusional infestation.”
MRI studies
Recent structural brain MRI studies support the concept that impaired somatosensory neural networks mediate the delusional symptoms of DI, but not in delusional disorders without somatic content. This was demonstrated in an MRI study by Dr. Lepping and others conducted in 18 patients with DI, 19 others with nonsomatic delusional disorders centered on themes of persecution or jealousy, and 20 healthy volunteers. The DI group had lower gray matter volume in prefrontal, thalamic, striatal, and insular regions of the brain compared to the other two groups.
Of note, mapping of the insula and dorsal striatum indicates they are part of the peripersonal space network, which integrates tactile and visual perceptions involving the area near the body surface. The insula also mediates feelings of pain and disgust.
Some of the same investigators have also recently reported brain MRI evidence specifically of cerebellar dysfunction in patients with DI, who displayed decreased gray matter volume in left lobule VIIa of the cerebellum and increased gray matter volume in bilateral lobule VIIa/crus II compared to patients with non-somatic delusions. This points to a role for impaired cerebellar neural networks related to somatosensory perception in patients with DI but not in those with non-somatic delusions.
Delusional infestation: What’s in a name?
Ekbom syndrome. Delusional parasitosis. Morgellons syndrome. These and other terms are increasingly giving way to ‘delusional infestation’ as the preferred moniker for the disorder. That’s in part because the delusional focus in patients with this condition has shifted over time. In the 19th century, for example, affected patients often attributed their infestation to typhus.
In contemporary practice, roughly one-quarter of affected patients think they are infested by small inanimate objects, most commonly fibers or threads emerging from the skin, rather than by parasites, insects, or worms. In a study of 148 consecutive European patients with suspected DI, Dr. Lepping and coinvestigators reported only 35% believed they were infested by parasites.
“The name ‘delusional infestation’ emphasizes the constantly changing pathogens and covers all present and future variations of the theme that are bound to occur,” Dr. Lepping observed.
All speakers reported having no conflicts of interest.
Schizophrenia spectrum disorder is associated with a significantly increased risk of dying from COVID-19, new research shows.
Dr. Donald Goff
After adjusting for demographic and medical risk factors, the investigators found that patients who had been diagnosed with schizophrenia were two to three times more likely to die of COVID-19 if they contracted the disease.
“This means that people with schizophrenia should be prioritized for vaccination, and efforts should be taken to reduce risk of infection [social distancing, masks, etc.], particularly in people with schizophrenia who live in congregate living situations [hospitals and group residences],” Donald Goff, MD, department of psychiatry, New York University Langone Medical Center, said in an interview.
The study included 7,348 adults with laboratory-confirmed SARS-CoV-2 infection from the NYU Langone Health System; 75 (1.0%) had a history of schizophrenia spectrum disorder, 564 (7.7%) had a history of a mood disorder, and 360 (4.9%) had a history of an anxiety disorder.
Overall, 864 patients (11.8%) died or were discharged to hospice within 45 days of a positive SARS-CoV-2 test.
In the fully adjusted model, a premorbid diagnosis of schizophrenia spectrum disorder, but not mood or anxiety disorder, was significantly associated with an increased risk of dying from COVID-19 within 45 days.
”A higher risk with schizophrenia spectrum diagnoses was expected based on previous studies of all-cause mortality, but the magnitude of the increase after adjusting for comorbid medical risk factors was unexpected,” the researchers wrote in the study, first authored by Katlyn Nemani, MD, research assistant professor of psychiatry at NYU Langone.
‘Alarming finding’
In an interview, Luming Li, MD, Yale New Haven (Conn.) Psychiatric Hospital, noted that, although the number patients with schizophrenia spectrum disorders in the sample is “fairly low,” she was not surprised by the increased risk for death from COVID-19.
Dr. Luming Li
“Schizophrenia falls into the serious mental illness category, and these patients are more often predisposed to homelessness, comorbid medical and substance use, living in congregate settings, lower socioeconomic status, etc,” Dr. Li noted.
Dr. Li’s advice for clinicians who treat patients who have schizophrenia during the COVID-19 pandemic is to minimize their risk in various care settings through the use of personal protective equipment and other infection prevention techniques.
“If a patient does contract COVID-19, make sure patient’s care is escalated appropriately, given the higher risk for mortality in patients with schizophrenia spectrum disorders,” she said.
Tom Pollak, PhD, MRCPsych, King’s College London, said that it has been known for some time that patients with serious mental illness have poorer physical health outcomes. More recently, it has been shown that those who have been diagnosed with psychiatric disorders appear to be at greater risk for poor COVID-19 outcomes.
“This study is the first to specifically highlight schizophrenia spectrum disorders as being particularly at risk. This is an alarming finding. These patients are already amongst the most vulnerable members of society and are probably underserved by most health care systems worldwide,” Dr. Pollak said in a statement.
“Although these findings need urgent replication in larger samples, there are clear reasons for policymakers to take notice now, including giving immediate consideration for prioritization of patients with serious mental illness in nationwide COVID-19 vaccination programs,” he added.
Matthew Hotopf, PhD, FRCPsych, FMedSci, also with King’s College London, said that the New York group has identified people with severe mental disorders as “a high-risk group, and this has immediate public health implications regarding vaccination – that’s the important message of the paper.
“Schizophrenia and other severe psychiatric disorders are risk factors for mortality in the general population before COVID. This is a group with a 10- to 20-year reduction in life expectancy – more than for many diseases we associated with early death,” said Dr. Hotopf.
“The reasons for this are multifactorial, including social deprivation, lifestyle factors (people with schizophrenia smoke more and have high rates of obesity), harms associated with some medications used to treat psychosis, and differential access to health care,” he noted.
“In COVID, we know that deprivation is associated with a much higher mortality, so we would therefore expect that people with severe mental illness will be particularly disadvantaged,” he said.
The study had no specific funding. Dr. Goff has received research support and travel reimbursement from Avanir Pharmaceuticals and Takeda. Dr. Nemani, Dr. Li, Dr. Pollak, and Dr. Hotopf disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Schizophrenia spectrum disorder is associated with a significantly increased risk of dying from COVID-19, new research shows.
Dr. Donald Goff
After adjusting for demographic and medical risk factors, the investigators found that patients who had been diagnosed with schizophrenia were two to three times more likely to die of COVID-19 if they contracted the disease.
“This means that people with schizophrenia should be prioritized for vaccination, and efforts should be taken to reduce risk of infection [social distancing, masks, etc.], particularly in people with schizophrenia who live in congregate living situations [hospitals and group residences],” Donald Goff, MD, department of psychiatry, New York University Langone Medical Center, said in an interview.
The study included 7,348 adults with laboratory-confirmed SARS-CoV-2 infection from the NYU Langone Health System; 75 (1.0%) had a history of schizophrenia spectrum disorder, 564 (7.7%) had a history of a mood disorder, and 360 (4.9%) had a history of an anxiety disorder.
Overall, 864 patients (11.8%) died or were discharged to hospice within 45 days of a positive SARS-CoV-2 test.
In the fully adjusted model, a premorbid diagnosis of schizophrenia spectrum disorder, but not mood or anxiety disorder, was significantly associated with an increased risk of dying from COVID-19 within 45 days.
”A higher risk with schizophrenia spectrum diagnoses was expected based on previous studies of all-cause mortality, but the magnitude of the increase after adjusting for comorbid medical risk factors was unexpected,” the researchers wrote in the study, first authored by Katlyn Nemani, MD, research assistant professor of psychiatry at NYU Langone.
‘Alarming finding’
In an interview, Luming Li, MD, Yale New Haven (Conn.) Psychiatric Hospital, noted that, although the number patients with schizophrenia spectrum disorders in the sample is “fairly low,” she was not surprised by the increased risk for death from COVID-19.
Dr. Luming Li
“Schizophrenia falls into the serious mental illness category, and these patients are more often predisposed to homelessness, comorbid medical and substance use, living in congregate settings, lower socioeconomic status, etc,” Dr. Li noted.
Dr. Li’s advice for clinicians who treat patients who have schizophrenia during the COVID-19 pandemic is to minimize their risk in various care settings through the use of personal protective equipment and other infection prevention techniques.
“If a patient does contract COVID-19, make sure patient’s care is escalated appropriately, given the higher risk for mortality in patients with schizophrenia spectrum disorders,” she said.
Tom Pollak, PhD, MRCPsych, King’s College London, said that it has been known for some time that patients with serious mental illness have poorer physical health outcomes. More recently, it has been shown that those who have been diagnosed with psychiatric disorders appear to be at greater risk for poor COVID-19 outcomes.
“This study is the first to specifically highlight schizophrenia spectrum disorders as being particularly at risk. This is an alarming finding. These patients are already amongst the most vulnerable members of society and are probably underserved by most health care systems worldwide,” Dr. Pollak said in a statement.
“Although these findings need urgent replication in larger samples, there are clear reasons for policymakers to take notice now, including giving immediate consideration for prioritization of patients with serious mental illness in nationwide COVID-19 vaccination programs,” he added.
Matthew Hotopf, PhD, FRCPsych, FMedSci, also with King’s College London, said that the New York group has identified people with severe mental disorders as “a high-risk group, and this has immediate public health implications regarding vaccination – that’s the important message of the paper.
“Schizophrenia and other severe psychiatric disorders are risk factors for mortality in the general population before COVID. This is a group with a 10- to 20-year reduction in life expectancy – more than for many diseases we associated with early death,” said Dr. Hotopf.
“The reasons for this are multifactorial, including social deprivation, lifestyle factors (people with schizophrenia smoke more and have high rates of obesity), harms associated with some medications used to treat psychosis, and differential access to health care,” he noted.
“In COVID, we know that deprivation is associated with a much higher mortality, so we would therefore expect that people with severe mental illness will be particularly disadvantaged,” he said.
The study had no specific funding. Dr. Goff has received research support and travel reimbursement from Avanir Pharmaceuticals and Takeda. Dr. Nemani, Dr. Li, Dr. Pollak, and Dr. Hotopf disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Schizophrenia spectrum disorder is associated with a significantly increased risk of dying from COVID-19, new research shows.
Dr. Donald Goff
After adjusting for demographic and medical risk factors, the investigators found that patients who had been diagnosed with schizophrenia were two to three times more likely to die of COVID-19 if they contracted the disease.
“This means that people with schizophrenia should be prioritized for vaccination, and efforts should be taken to reduce risk of infection [social distancing, masks, etc.], particularly in people with schizophrenia who live in congregate living situations [hospitals and group residences],” Donald Goff, MD, department of psychiatry, New York University Langone Medical Center, said in an interview.
The study included 7,348 adults with laboratory-confirmed SARS-CoV-2 infection from the NYU Langone Health System; 75 (1.0%) had a history of schizophrenia spectrum disorder, 564 (7.7%) had a history of a mood disorder, and 360 (4.9%) had a history of an anxiety disorder.
Overall, 864 patients (11.8%) died or were discharged to hospice within 45 days of a positive SARS-CoV-2 test.
In the fully adjusted model, a premorbid diagnosis of schizophrenia spectrum disorder, but not mood or anxiety disorder, was significantly associated with an increased risk of dying from COVID-19 within 45 days.
”A higher risk with schizophrenia spectrum diagnoses was expected based on previous studies of all-cause mortality, but the magnitude of the increase after adjusting for comorbid medical risk factors was unexpected,” the researchers wrote in the study, first authored by Katlyn Nemani, MD, research assistant professor of psychiatry at NYU Langone.
‘Alarming finding’
In an interview, Luming Li, MD, Yale New Haven (Conn.) Psychiatric Hospital, noted that, although the number patients with schizophrenia spectrum disorders in the sample is “fairly low,” she was not surprised by the increased risk for death from COVID-19.
Dr. Luming Li
“Schizophrenia falls into the serious mental illness category, and these patients are more often predisposed to homelessness, comorbid medical and substance use, living in congregate settings, lower socioeconomic status, etc,” Dr. Li noted.
Dr. Li’s advice for clinicians who treat patients who have schizophrenia during the COVID-19 pandemic is to minimize their risk in various care settings through the use of personal protective equipment and other infection prevention techniques.
“If a patient does contract COVID-19, make sure patient’s care is escalated appropriately, given the higher risk for mortality in patients with schizophrenia spectrum disorders,” she said.
Tom Pollak, PhD, MRCPsych, King’s College London, said that it has been known for some time that patients with serious mental illness have poorer physical health outcomes. More recently, it has been shown that those who have been diagnosed with psychiatric disorders appear to be at greater risk for poor COVID-19 outcomes.
“This study is the first to specifically highlight schizophrenia spectrum disorders as being particularly at risk. This is an alarming finding. These patients are already amongst the most vulnerable members of society and are probably underserved by most health care systems worldwide,” Dr. Pollak said in a statement.
“Although these findings need urgent replication in larger samples, there are clear reasons for policymakers to take notice now, including giving immediate consideration for prioritization of patients with serious mental illness in nationwide COVID-19 vaccination programs,” he added.
Matthew Hotopf, PhD, FRCPsych, FMedSci, also with King’s College London, said that the New York group has identified people with severe mental disorders as “a high-risk group, and this has immediate public health implications regarding vaccination – that’s the important message of the paper.
“Schizophrenia and other severe psychiatric disorders are risk factors for mortality in the general population before COVID. This is a group with a 10- to 20-year reduction in life expectancy – more than for many diseases we associated with early death,” said Dr. Hotopf.
“The reasons for this are multifactorial, including social deprivation, lifestyle factors (people with schizophrenia smoke more and have high rates of obesity), harms associated with some medications used to treat psychosis, and differential access to health care,” he noted.
“In COVID, we know that deprivation is associated with a much higher mortality, so we would therefore expect that people with severe mental illness will be particularly disadvantaged,” he said.
The study had no specific funding. Dr. Goff has received research support and travel reimbursement from Avanir Pharmaceuticals and Takeda. Dr. Nemani, Dr. Li, Dr. Pollak, and Dr. Hotopf disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Long-acting injectable antipsychotics (LAIs) are an essential tool in the treatment of patients with psychotic disorders, allowing for periods of stable drug plasma concentration and confirmed adherence.1 The current coronavirus disease 2019 (COVID-19) pandemic presents unique challenges for administering LAIs and requires a thoughtful and prospective approach in order to ensure continuity of psychiatric care while minimizing the risk of infection with COVID-19. Ideally, patients should be seen in person as infrequently as clinically prudent during this public health emergency; however, LAI administration necessitates direct physical contact between patient and clinician.
Patients with serious mental illness (SMI), who comprise the majority of individuals who receive LAIs, are at heightened risk for cardiovascular and pulmonary comorbidities. These factors are the primary reason the life expectancy of a patient with SMI is nearly 30 years shorter than that of the general population.2-5 The risk of health care workers becoming infected or inadvertently spreading COVID-19 is heightened when working with patients in group living environments (ie, a shelter or group home), who have both increased exposure and increased risk of further transmission.6 Additional patient populations, including older adults, immunocompromised individuals, and those with preexisting conditions, are at heightened risk for serious complications if they were to contract COVID-19.7,8
Thus, the questions of whether LAIs should be administered, and how to do so safely (both during the ongoing, acute phase of the pandemic as well as during the subsequent recovery period until the pandemic abates) need to be carefully considered. In this article, we provide concrete advice for clinicians and clinics on these topics, with the goal of maintaining patients’ psychiatric stability while protecting patients, health care workers, and the broader society from COVID-19 infection. Table 1 summarizes the questions regarding LAIs that clinicians need to address during this crisis. While we focus on outpatient care, inpatient teams should keep these considerations in mind if they are starting and discharging a patient on an LAI. More than ever, close collaboration and communication between inpatient and outpatient teams is critical.
Should an LAI be continued?
An important first step to approaching this challenge is to create a spreadsheet for all patients receiving LAIs. Focusing on a population-based approach is helpful to be systematic and ensure that no patients fall through the cracks during this public health emergency.9 Once all patients have been identified, the treatment team should review each patient to determine if continuing to administer the antipsychotic as an LAI formulation is essential, taking into account the patient’s current psychiatric status, historical medication adherence, potential severity and dangerousness of decompensation if nonadherent, and structures to support stability. For example, can a patient move in with family who can monitor medication adherence during the pandemic? Is it possible for the group home to assume medication administration? Additional consideration should be given to the living environment and health-vulnerability of the patient and the individuals living with them.
If the risk calculation does not point strongly towards a need for continuing the LAI, it may be prudent to temporarily transition the patient to the corresponding oral antipsychotic preparation. Table 2lists all LAIs available in the United States and their approximate equivalent oral dosing. It is important to note that such transitions are not without clinical risk, to emphasize to the patient that the transition is intended as a temporary measure, and to discuss a proposed timeline for re-initiating the LAI. Also, emphasize to the patient and family that this transition does not diminish the previous reasoning for needing an LAI, but is a temporary measure taken in light of weighing the risks and benefits during a pandemic.
Which LAI should be administered?
If continuing the LAI is determined to be clinically necessary, consider switching the patient to a longer-acting preparation to maximize intervals between administrations and minimize the potential for infection. From a public health perspective, the longest clinically prudent interval between injections may be the most important consideration, provided the patient can receive a dose necessary to retain stability, and the LAI should be chosen accordingly. Deltoid injections may be able to be administered with reduced contact, or on a “drive-up” basis.10 Consider transitioning a patient who is receiving olanzapine pamoate to an alternate LAI or oral formulation, because the 3-hour observation period that is required after olanzapine pamoate administration is particularly problematic. While it may not be ideal to make medication changes during a pandemic, it is worth carefully weighing the patient’s stability and historical experience with other LAIs to determine if a safer/longer-spaced option is worth trying.11
We recommend only switching among similar antipsychotics (ie, risperidone to paliperidone), or between different preparations of the same drug (ie, Abilify Maintena to Aristada), if possible, as these are the lowest risk transitions with regards to relapse. Table 3provides examples.
Continue to: When should the LAI be administered?
When should the LAI be administered?
The pharmacokinetics of LAIs allow for some flexibility in terms of when an LAI needs to be administered. The package inserts of all second-generation LAIs include missed-dose guidelines. These guidelines provide information on how long one can wait before the next injection is due, and what additional measures must be taken when beyond that date. Delaying an injection may be prudent, and the missed dose guidelines will indicate when one must consider supplementing with oral medications. For patients who are in quarantine, it may be better to delay an injection until the patient ends their quarantine than to deliver the dose during quarantine. Administering an injection earlier also is usually safe; off-cycle visits may help minimize patient contact (ie, if the patient happens to be coming into the vicinity of the clinic, or requires phlebotomy for therapeutic drug monitoring), and assist in planning for possible resurgences. When appropriate, and after considering the risk of worsening adverse effects, administering a higher dose than the usual maintenance dose would provide a buffer if the next injection was to be delayed. Therapeutic drug monitoring can help to optimize dosing and avoid low plasma drug levels, which may be not be sufficient, particularly during this time of stress.12 To provide optimal protection against relapse, consider administering a dose that puts patients at the higher range of plasma drug levels.
Where can the LAI be administered, and who can give it?
For patients who usually travel to a clinic, consider arranging for a more local injection (ie, at the patient’s primary care clinic in their hometown, or at a local mental health center), and explore if the patient may be able to receive their injection in their home through a visiting nurse association (VNA). In many states (approximately 30 currently), clinicians at pharmacies are also able to administer patient injections. Clinics would do well to at least plan for alternate staffing models in the event of staff illness. A pool of individuals should be available to give injections; consider training additional staff members (including MDs who may have never previously administered an LAI but could be quickly instructed to do so) to administer LAIs. Theoretically, during a public health emergency, family members, particularly those who have a background in health care, could be trained to give an injection and provided education on LAI storage and post-injection monitoring. This approach would not be consistent with FDA labeling, however, and should only be considered as a last resort.
What safety measures can be put in place?
Face-to-face time for injection administration should be kept as brief as possible. Before the encounter, obtain the patient’s clinical information, ideally through telehealth or from an acceptable distance. Medication should be drawn ahead of time, and not in an enclosed space with the patient present. Strongly consider abandoning the traditional enclosed room for the injection, and instead use larger spaces, doorways, or outside, if feasible. As previously noted, some clinics and clinicians have used a drive-up approach for LAI administration, particularly for deltoid injections.10 Individuals who administer the injections should wear personal protective equipment, and the clinic should obtain an adequate supply of this equipment well in advance.
Lessons learned at our clinic
In our community mental health center clinic, planning around these questions has allowed us to provide safe and continuous psychiatric care with LAIs during this public health emergency while reducing the risk of infection. We have worked to transfer LAI administration to VNAs and transition patients to longer-lasting formulations or oral medications where appropriate, which has resulted in an approximately 50% decrease in in-person visits. Reducing the number of in-person visits does not need to result in less frequent clinical follow-up. Telepsychiatry visits can make up for lost in-person visits and have generally been well accepted.
As we are preparing for the next phase, routine medical health monitoring (eg, metabolic monitoring, monitoring for tardive dyskinesia) that has not been at the forefront of concerns should be carefully reintroduced. Challenges encountered have included difficulty in having VNA accept patients for short-term LAI visits, changes to where on the body the injection is delivered, and patients with SMI and their families being reluctant to depart from previous routines and administration schedules.
Continue to: There is great value...
There is great value in the collective lessons learned during this public health emergency (eg, the need for a flexible, population health-based approach; acceptability of combination telehealth and in-person visits) that can lead to more person-centered and accessible care for patients with SMI.
Acknowledgments
The authors thank North Suffolk Mental Health Association, the Freedom Trail Clinic, and their patients.
Bottom Line
When caring for a patient with a psychotic illness during the coronavirus disease 2019 (COVID-19) pandemic, evaluate whether it is necessary to continue a longacting injectable antipsychotic (LAI). If yes, reconsider which LAI should be administered, when and where it should be given, and by whom. Implement safety measures to minimize the risk of COVID-19 exposure and transmission.
1. Freudenreich O. Long-acting injectable antipsychotics. In: Freudenreich O. Psychotic disorders: a practical guide. Springer; 2020:249-261. 2. Olfson M, Gerhard T, Huang C, et al. Premature mortality among adults with schizophrenia in the United States. JAMA Psychiatry. 2015;72(12):1172-1181. 3. Reilly S, Olier I, Planner C, et al. Inequalities in physical comorbidity: a longitudinal comparative cohort study of people with severe mental illness in the UK. BMJ Open. 2015;5(12):e009010. 4. Brown S, Inskip H, Barraclough B. Causes of the excess mortality of schizophrenia. Br J Psychiatry. 2000;177:212-217. 5. Goff DC, Cather C, Evins AE, et al. Medical morbidity and mortality in schizophrenia: guidelines for psychiatrists. J Clin Psychiatry. 2005;66(2):183-194. 6. Baggett TP, Keyes H, Sporn N, et al. Prevalence of SARS-CoV-2 infection in residents of a large homeless shelter in Boston. JAMA. 2020;323(21):2191-2192. 7. CDC COVID-19 Response Team. Severe outcomes among patients with coronavirus disease 2019 (COVID-19)—United States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(12):343-346. 8. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. 2020;369:m1985. doi: 10.1136/bmj.m1985 9. Etches V, Frank J, Di Ruggiero E, et al. Measuring population health: a review of indicators. Annu Rev Public Health. 2006;27:29-55. 10. Chepke C. Drive-up pharmacotherapy during the COVID-19 pandemic. Current Psychiatry. 2020;19(5):29-30. 11. Sajatovic M, Ross R, Legacy SN, et al. Initiating/maintaining long-acting injectable antipsychotics in schizophrenia/schizoaffective or bipolar disorder - expert consensus survey part 2. Neuropsychiatr Dis Treat. 2018;14:1475-1492. 12. Schoretsanitis G, Kane JM, Correll CU, et al; American Society of Clinical Psychopharmacology, Pharmakopsychiatrie TTDMTFOTAFNU. Blood levels to optimize antipsychotic treatment in clinical practice: a joint consensus statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie. J Clin Psychiatry. 2020;81(3):19cs13169. doi: 10.4088/JCP.19cs13169
Kristina Schnitzer, MD Fellow, Public and Community Psychiatry Massachusetts General Hospital Boston, Massachusetts
Sarah MacLaurin, PMHNP-BC Freedom Trail Clinic of North Suffolk Mental Health Association Massachusetts General Hospital Boston, Massachusetts
Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Clinical and Research Program Associate Professor of Psychiatry Harvard Medical School Boston, Massachusetts
Disclosures Dr. Freudenreich has received grant or research support from Alkermes, Avanir, Janssen, Otsuka, and Saladax, and has served as a consultant to Alkermes, Janssen, Neurocrine, Novartis, and Roche. Drs. Schnitzer and MacLaurin report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.
Kristina Schnitzer, MD Fellow, Public and Community Psychiatry Massachusetts General Hospital Boston, Massachusetts
Sarah MacLaurin, PMHNP-BC Freedom Trail Clinic of North Suffolk Mental Health Association Massachusetts General Hospital Boston, Massachusetts
Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Clinical and Research Program Associate Professor of Psychiatry Harvard Medical School Boston, Massachusetts
Disclosures Dr. Freudenreich has received grant or research support from Alkermes, Avanir, Janssen, Otsuka, and Saladax, and has served as a consultant to Alkermes, Janssen, Neurocrine, Novartis, and Roche. Drs. Schnitzer and MacLaurin report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.
Author and Disclosure Information
Kristina Schnitzer, MD Fellow, Public and Community Psychiatry Massachusetts General Hospital Boston, Massachusetts
Sarah MacLaurin, PMHNP-BC Freedom Trail Clinic of North Suffolk Mental Health Association Massachusetts General Hospital Boston, Massachusetts
Oliver Freudenreich, MD, FACLP Co-Director, MGH Schizophrenia Clinical and Research Program Associate Professor of Psychiatry Harvard Medical School Boston, Massachusetts
Disclosures Dr. Freudenreich has received grant or research support from Alkermes, Avanir, Janssen, Otsuka, and Saladax, and has served as a consultant to Alkermes, Janssen, Neurocrine, Novartis, and Roche. Drs. Schnitzer and MacLaurin report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.
Long-acting injectable antipsychotics (LAIs) are an essential tool in the treatment of patients with psychotic disorders, allowing for periods of stable drug plasma concentration and confirmed adherence.1 The current coronavirus disease 2019 (COVID-19) pandemic presents unique challenges for administering LAIs and requires a thoughtful and prospective approach in order to ensure continuity of psychiatric care while minimizing the risk of infection with COVID-19. Ideally, patients should be seen in person as infrequently as clinically prudent during this public health emergency; however, LAI administration necessitates direct physical contact between patient and clinician.
Patients with serious mental illness (SMI), who comprise the majority of individuals who receive LAIs, are at heightened risk for cardiovascular and pulmonary comorbidities. These factors are the primary reason the life expectancy of a patient with SMI is nearly 30 years shorter than that of the general population.2-5 The risk of health care workers becoming infected or inadvertently spreading COVID-19 is heightened when working with patients in group living environments (ie, a shelter or group home), who have both increased exposure and increased risk of further transmission.6 Additional patient populations, including older adults, immunocompromised individuals, and those with preexisting conditions, are at heightened risk for serious complications if they were to contract COVID-19.7,8
Thus, the questions of whether LAIs should be administered, and how to do so safely (both during the ongoing, acute phase of the pandemic as well as during the subsequent recovery period until the pandemic abates) need to be carefully considered. In this article, we provide concrete advice for clinicians and clinics on these topics, with the goal of maintaining patients’ psychiatric stability while protecting patients, health care workers, and the broader society from COVID-19 infection. Table 1 summarizes the questions regarding LAIs that clinicians need to address during this crisis. While we focus on outpatient care, inpatient teams should keep these considerations in mind if they are starting and discharging a patient on an LAI. More than ever, close collaboration and communication between inpatient and outpatient teams is critical.
Should an LAI be continued?
An important first step to approaching this challenge is to create a spreadsheet for all patients receiving LAIs. Focusing on a population-based approach is helpful to be systematic and ensure that no patients fall through the cracks during this public health emergency.9 Once all patients have been identified, the treatment team should review each patient to determine if continuing to administer the antipsychotic as an LAI formulation is essential, taking into account the patient’s current psychiatric status, historical medication adherence, potential severity and dangerousness of decompensation if nonadherent, and structures to support stability. For example, can a patient move in with family who can monitor medication adherence during the pandemic? Is it possible for the group home to assume medication administration? Additional consideration should be given to the living environment and health-vulnerability of the patient and the individuals living with them.
If the risk calculation does not point strongly towards a need for continuing the LAI, it may be prudent to temporarily transition the patient to the corresponding oral antipsychotic preparation. Table 2lists all LAIs available in the United States and their approximate equivalent oral dosing. It is important to note that such transitions are not without clinical risk, to emphasize to the patient that the transition is intended as a temporary measure, and to discuss a proposed timeline for re-initiating the LAI. Also, emphasize to the patient and family that this transition does not diminish the previous reasoning for needing an LAI, but is a temporary measure taken in light of weighing the risks and benefits during a pandemic.
Which LAI should be administered?
If continuing the LAI is determined to be clinically necessary, consider switching the patient to a longer-acting preparation to maximize intervals between administrations and minimize the potential for infection. From a public health perspective, the longest clinically prudent interval between injections may be the most important consideration, provided the patient can receive a dose necessary to retain stability, and the LAI should be chosen accordingly. Deltoid injections may be able to be administered with reduced contact, or on a “drive-up” basis.10 Consider transitioning a patient who is receiving olanzapine pamoate to an alternate LAI or oral formulation, because the 3-hour observation period that is required after olanzapine pamoate administration is particularly problematic. While it may not be ideal to make medication changes during a pandemic, it is worth carefully weighing the patient’s stability and historical experience with other LAIs to determine if a safer/longer-spaced option is worth trying.11
We recommend only switching among similar antipsychotics (ie, risperidone to paliperidone), or between different preparations of the same drug (ie, Abilify Maintena to Aristada), if possible, as these are the lowest risk transitions with regards to relapse. Table 3provides examples.
Continue to: When should the LAI be administered?
When should the LAI be administered?
The pharmacokinetics of LAIs allow for some flexibility in terms of when an LAI needs to be administered. The package inserts of all second-generation LAIs include missed-dose guidelines. These guidelines provide information on how long one can wait before the next injection is due, and what additional measures must be taken when beyond that date. Delaying an injection may be prudent, and the missed dose guidelines will indicate when one must consider supplementing with oral medications. For patients who are in quarantine, it may be better to delay an injection until the patient ends their quarantine than to deliver the dose during quarantine. Administering an injection earlier also is usually safe; off-cycle visits may help minimize patient contact (ie, if the patient happens to be coming into the vicinity of the clinic, or requires phlebotomy for therapeutic drug monitoring), and assist in planning for possible resurgences. When appropriate, and after considering the risk of worsening adverse effects, administering a higher dose than the usual maintenance dose would provide a buffer if the next injection was to be delayed. Therapeutic drug monitoring can help to optimize dosing and avoid low plasma drug levels, which may be not be sufficient, particularly during this time of stress.12 To provide optimal protection against relapse, consider administering a dose that puts patients at the higher range of plasma drug levels.
Where can the LAI be administered, and who can give it?
For patients who usually travel to a clinic, consider arranging for a more local injection (ie, at the patient’s primary care clinic in their hometown, or at a local mental health center), and explore if the patient may be able to receive their injection in their home through a visiting nurse association (VNA). In many states (approximately 30 currently), clinicians at pharmacies are also able to administer patient injections. Clinics would do well to at least plan for alternate staffing models in the event of staff illness. A pool of individuals should be available to give injections; consider training additional staff members (including MDs who may have never previously administered an LAI but could be quickly instructed to do so) to administer LAIs. Theoretically, during a public health emergency, family members, particularly those who have a background in health care, could be trained to give an injection and provided education on LAI storage and post-injection monitoring. This approach would not be consistent with FDA labeling, however, and should only be considered as a last resort.
What safety measures can be put in place?
Face-to-face time for injection administration should be kept as brief as possible. Before the encounter, obtain the patient’s clinical information, ideally through telehealth or from an acceptable distance. Medication should be drawn ahead of time, and not in an enclosed space with the patient present. Strongly consider abandoning the traditional enclosed room for the injection, and instead use larger spaces, doorways, or outside, if feasible. As previously noted, some clinics and clinicians have used a drive-up approach for LAI administration, particularly for deltoid injections.10 Individuals who administer the injections should wear personal protective equipment, and the clinic should obtain an adequate supply of this equipment well in advance.
Lessons learned at our clinic
In our community mental health center clinic, planning around these questions has allowed us to provide safe and continuous psychiatric care with LAIs during this public health emergency while reducing the risk of infection. We have worked to transfer LAI administration to VNAs and transition patients to longer-lasting formulations or oral medications where appropriate, which has resulted in an approximately 50% decrease in in-person visits. Reducing the number of in-person visits does not need to result in less frequent clinical follow-up. Telepsychiatry visits can make up for lost in-person visits and have generally been well accepted.
As we are preparing for the next phase, routine medical health monitoring (eg, metabolic monitoring, monitoring for tardive dyskinesia) that has not been at the forefront of concerns should be carefully reintroduced. Challenges encountered have included difficulty in having VNA accept patients for short-term LAI visits, changes to where on the body the injection is delivered, and patients with SMI and their families being reluctant to depart from previous routines and administration schedules.
Continue to: There is great value...
There is great value in the collective lessons learned during this public health emergency (eg, the need for a flexible, population health-based approach; acceptability of combination telehealth and in-person visits) that can lead to more person-centered and accessible care for patients with SMI.
Acknowledgments
The authors thank North Suffolk Mental Health Association, the Freedom Trail Clinic, and their patients.
Bottom Line
When caring for a patient with a psychotic illness during the coronavirus disease 2019 (COVID-19) pandemic, evaluate whether it is necessary to continue a longacting injectable antipsychotic (LAI). If yes, reconsider which LAI should be administered, when and where it should be given, and by whom. Implement safety measures to minimize the risk of COVID-19 exposure and transmission.
Long-acting injectable antipsychotics (LAIs) are an essential tool in the treatment of patients with psychotic disorders, allowing for periods of stable drug plasma concentration and confirmed adherence.1 The current coronavirus disease 2019 (COVID-19) pandemic presents unique challenges for administering LAIs and requires a thoughtful and prospective approach in order to ensure continuity of psychiatric care while minimizing the risk of infection with COVID-19. Ideally, patients should be seen in person as infrequently as clinically prudent during this public health emergency; however, LAI administration necessitates direct physical contact between patient and clinician.
Patients with serious mental illness (SMI), who comprise the majority of individuals who receive LAIs, are at heightened risk for cardiovascular and pulmonary comorbidities. These factors are the primary reason the life expectancy of a patient with SMI is nearly 30 years shorter than that of the general population.2-5 The risk of health care workers becoming infected or inadvertently spreading COVID-19 is heightened when working with patients in group living environments (ie, a shelter or group home), who have both increased exposure and increased risk of further transmission.6 Additional patient populations, including older adults, immunocompromised individuals, and those with preexisting conditions, are at heightened risk for serious complications if they were to contract COVID-19.7,8
Thus, the questions of whether LAIs should be administered, and how to do so safely (both during the ongoing, acute phase of the pandemic as well as during the subsequent recovery period until the pandemic abates) need to be carefully considered. In this article, we provide concrete advice for clinicians and clinics on these topics, with the goal of maintaining patients’ psychiatric stability while protecting patients, health care workers, and the broader society from COVID-19 infection. Table 1 summarizes the questions regarding LAIs that clinicians need to address during this crisis. While we focus on outpatient care, inpatient teams should keep these considerations in mind if they are starting and discharging a patient on an LAI. More than ever, close collaboration and communication between inpatient and outpatient teams is critical.
Should an LAI be continued?
An important first step to approaching this challenge is to create a spreadsheet for all patients receiving LAIs. Focusing on a population-based approach is helpful to be systematic and ensure that no patients fall through the cracks during this public health emergency.9 Once all patients have been identified, the treatment team should review each patient to determine if continuing to administer the antipsychotic as an LAI formulation is essential, taking into account the patient’s current psychiatric status, historical medication adherence, potential severity and dangerousness of decompensation if nonadherent, and structures to support stability. For example, can a patient move in with family who can monitor medication adherence during the pandemic? Is it possible for the group home to assume medication administration? Additional consideration should be given to the living environment and health-vulnerability of the patient and the individuals living with them.
If the risk calculation does not point strongly towards a need for continuing the LAI, it may be prudent to temporarily transition the patient to the corresponding oral antipsychotic preparation. Table 2lists all LAIs available in the United States and their approximate equivalent oral dosing. It is important to note that such transitions are not without clinical risk, to emphasize to the patient that the transition is intended as a temporary measure, and to discuss a proposed timeline for re-initiating the LAI. Also, emphasize to the patient and family that this transition does not diminish the previous reasoning for needing an LAI, but is a temporary measure taken in light of weighing the risks and benefits during a pandemic.
Which LAI should be administered?
If continuing the LAI is determined to be clinically necessary, consider switching the patient to a longer-acting preparation to maximize intervals between administrations and minimize the potential for infection. From a public health perspective, the longest clinically prudent interval between injections may be the most important consideration, provided the patient can receive a dose necessary to retain stability, and the LAI should be chosen accordingly. Deltoid injections may be able to be administered with reduced contact, or on a “drive-up” basis.10 Consider transitioning a patient who is receiving olanzapine pamoate to an alternate LAI or oral formulation, because the 3-hour observation period that is required after olanzapine pamoate administration is particularly problematic. While it may not be ideal to make medication changes during a pandemic, it is worth carefully weighing the patient’s stability and historical experience with other LAIs to determine if a safer/longer-spaced option is worth trying.11
We recommend only switching among similar antipsychotics (ie, risperidone to paliperidone), or between different preparations of the same drug (ie, Abilify Maintena to Aristada), if possible, as these are the lowest risk transitions with regards to relapse. Table 3provides examples.
Continue to: When should the LAI be administered?
When should the LAI be administered?
The pharmacokinetics of LAIs allow for some flexibility in terms of when an LAI needs to be administered. The package inserts of all second-generation LAIs include missed-dose guidelines. These guidelines provide information on how long one can wait before the next injection is due, and what additional measures must be taken when beyond that date. Delaying an injection may be prudent, and the missed dose guidelines will indicate when one must consider supplementing with oral medications. For patients who are in quarantine, it may be better to delay an injection until the patient ends their quarantine than to deliver the dose during quarantine. Administering an injection earlier also is usually safe; off-cycle visits may help minimize patient contact (ie, if the patient happens to be coming into the vicinity of the clinic, or requires phlebotomy for therapeutic drug monitoring), and assist in planning for possible resurgences. When appropriate, and after considering the risk of worsening adverse effects, administering a higher dose than the usual maintenance dose would provide a buffer if the next injection was to be delayed. Therapeutic drug monitoring can help to optimize dosing and avoid low plasma drug levels, which may be not be sufficient, particularly during this time of stress.12 To provide optimal protection against relapse, consider administering a dose that puts patients at the higher range of plasma drug levels.
Where can the LAI be administered, and who can give it?
For patients who usually travel to a clinic, consider arranging for a more local injection (ie, at the patient’s primary care clinic in their hometown, or at a local mental health center), and explore if the patient may be able to receive their injection in their home through a visiting nurse association (VNA). In many states (approximately 30 currently), clinicians at pharmacies are also able to administer patient injections. Clinics would do well to at least plan for alternate staffing models in the event of staff illness. A pool of individuals should be available to give injections; consider training additional staff members (including MDs who may have never previously administered an LAI but could be quickly instructed to do so) to administer LAIs. Theoretically, during a public health emergency, family members, particularly those who have a background in health care, could be trained to give an injection and provided education on LAI storage and post-injection monitoring. This approach would not be consistent with FDA labeling, however, and should only be considered as a last resort.
What safety measures can be put in place?
Face-to-face time for injection administration should be kept as brief as possible. Before the encounter, obtain the patient’s clinical information, ideally through telehealth or from an acceptable distance. Medication should be drawn ahead of time, and not in an enclosed space with the patient present. Strongly consider abandoning the traditional enclosed room for the injection, and instead use larger spaces, doorways, or outside, if feasible. As previously noted, some clinics and clinicians have used a drive-up approach for LAI administration, particularly for deltoid injections.10 Individuals who administer the injections should wear personal protective equipment, and the clinic should obtain an adequate supply of this equipment well in advance.
Lessons learned at our clinic
In our community mental health center clinic, planning around these questions has allowed us to provide safe and continuous psychiatric care with LAIs during this public health emergency while reducing the risk of infection. We have worked to transfer LAI administration to VNAs and transition patients to longer-lasting formulations or oral medications where appropriate, which has resulted in an approximately 50% decrease in in-person visits. Reducing the number of in-person visits does not need to result in less frequent clinical follow-up. Telepsychiatry visits can make up for lost in-person visits and have generally been well accepted.
As we are preparing for the next phase, routine medical health monitoring (eg, metabolic monitoring, monitoring for tardive dyskinesia) that has not been at the forefront of concerns should be carefully reintroduced. Challenges encountered have included difficulty in having VNA accept patients for short-term LAI visits, changes to where on the body the injection is delivered, and patients with SMI and their families being reluctant to depart from previous routines and administration schedules.
Continue to: There is great value...
There is great value in the collective lessons learned during this public health emergency (eg, the need for a flexible, population health-based approach; acceptability of combination telehealth and in-person visits) that can lead to more person-centered and accessible care for patients with SMI.
Acknowledgments
The authors thank North Suffolk Mental Health Association, the Freedom Trail Clinic, and their patients.
Bottom Line
When caring for a patient with a psychotic illness during the coronavirus disease 2019 (COVID-19) pandemic, evaluate whether it is necessary to continue a longacting injectable antipsychotic (LAI). If yes, reconsider which LAI should be administered, when and where it should be given, and by whom. Implement safety measures to minimize the risk of COVID-19 exposure and transmission.
1. Freudenreich O. Long-acting injectable antipsychotics. In: Freudenreich O. Psychotic disorders: a practical guide. Springer; 2020:249-261. 2. Olfson M, Gerhard T, Huang C, et al. Premature mortality among adults with schizophrenia in the United States. JAMA Psychiatry. 2015;72(12):1172-1181. 3. Reilly S, Olier I, Planner C, et al. Inequalities in physical comorbidity: a longitudinal comparative cohort study of people with severe mental illness in the UK. BMJ Open. 2015;5(12):e009010. 4. Brown S, Inskip H, Barraclough B. Causes of the excess mortality of schizophrenia. Br J Psychiatry. 2000;177:212-217. 5. Goff DC, Cather C, Evins AE, et al. Medical morbidity and mortality in schizophrenia: guidelines for psychiatrists. J Clin Psychiatry. 2005;66(2):183-194. 6. Baggett TP, Keyes H, Sporn N, et al. Prevalence of SARS-CoV-2 infection in residents of a large homeless shelter in Boston. JAMA. 2020;323(21):2191-2192. 7. CDC COVID-19 Response Team. Severe outcomes among patients with coronavirus disease 2019 (COVID-19)—United States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(12):343-346. 8. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. 2020;369:m1985. doi: 10.1136/bmj.m1985 9. Etches V, Frank J, Di Ruggiero E, et al. Measuring population health: a review of indicators. Annu Rev Public Health. 2006;27:29-55. 10. Chepke C. Drive-up pharmacotherapy during the COVID-19 pandemic. Current Psychiatry. 2020;19(5):29-30. 11. Sajatovic M, Ross R, Legacy SN, et al. Initiating/maintaining long-acting injectable antipsychotics in schizophrenia/schizoaffective or bipolar disorder - expert consensus survey part 2. Neuropsychiatr Dis Treat. 2018;14:1475-1492. 12. Schoretsanitis G, Kane JM, Correll CU, et al; American Society of Clinical Psychopharmacology, Pharmakopsychiatrie TTDMTFOTAFNU. Blood levels to optimize antipsychotic treatment in clinical practice: a joint consensus statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie. J Clin Psychiatry. 2020;81(3):19cs13169. doi: 10.4088/JCP.19cs13169
References
1. Freudenreich O. Long-acting injectable antipsychotics. In: Freudenreich O. Psychotic disorders: a practical guide. Springer; 2020:249-261. 2. Olfson M, Gerhard T, Huang C, et al. Premature mortality among adults with schizophrenia in the United States. JAMA Psychiatry. 2015;72(12):1172-1181. 3. Reilly S, Olier I, Planner C, et al. Inequalities in physical comorbidity: a longitudinal comparative cohort study of people with severe mental illness in the UK. BMJ Open. 2015;5(12):e009010. 4. Brown S, Inskip H, Barraclough B. Causes of the excess mortality of schizophrenia. Br J Psychiatry. 2000;177:212-217. 5. Goff DC, Cather C, Evins AE, et al. Medical morbidity and mortality in schizophrenia: guidelines for psychiatrists. J Clin Psychiatry. 2005;66(2):183-194. 6. Baggett TP, Keyes H, Sporn N, et al. Prevalence of SARS-CoV-2 infection in residents of a large homeless shelter in Boston. JAMA. 2020;323(21):2191-2192. 7. CDC COVID-19 Response Team. Severe outcomes among patients with coronavirus disease 2019 (COVID-19)—United States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(12):343-346. 8. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. 2020;369:m1985. doi: 10.1136/bmj.m1985 9. Etches V, Frank J, Di Ruggiero E, et al. Measuring population health: a review of indicators. Annu Rev Public Health. 2006;27:29-55. 10. Chepke C. Drive-up pharmacotherapy during the COVID-19 pandemic. Current Psychiatry. 2020;19(5):29-30. 11. Sajatovic M, Ross R, Legacy SN, et al. Initiating/maintaining long-acting injectable antipsychotics in schizophrenia/schizoaffective or bipolar disorder - expert consensus survey part 2. Neuropsychiatr Dis Treat. 2018;14:1475-1492. 12. Schoretsanitis G, Kane JM, Correll CU, et al; American Society of Clinical Psychopharmacology, Pharmakopsychiatrie TTDMTFOTAFNU. Blood levels to optimize antipsychotic treatment in clinical practice: a joint consensus statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie. J Clin Psychiatry. 2020;81(3):19cs13169. doi: 10.4088/JCP.19cs13169
